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Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma

Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma
Authors:
Yanming Zhang, MD
Michelle M Le Beau, PhD
Jon C Aster, MD, PhD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Jul 29, 2022.

INTRODUCTION — Acute lymphoblastic leukemia/lymphoma (ALL/LBL) refers to hematologic malignancies of lymphoid precursor cells. These entities are described as ALL/LBL because in this setting, leukemia and lymphoma are overlapping clinical presentations of the same disease; the systems for diagnosis and classification do not distinguish between leukemia and lymphoma. Broadly, ALL/LBL is divided into tumors of B cell and T cell lineage; rare tumors of natural killer (NK) cell lineage are also recognized. Immunophenotyping is required to determine the lineage of ALL/LBL because the different subtypes are morphologically indistinguishable.

Most cases of ALL/LBL have cytogenetic and/or molecular abnormalities that are associated with distinctive phenotypes, prognostic features, and/or influence the choice of treatment. The World Health Organization (WHO) classification system uses immunophenotype and cytogenetic/molecular features to define specific categories of ALL/LBL [1]. This topic will review the WHO classification of ALL/LBL and the associated cytogenetic and molecular abnormalities.

Clinical manifestations, evaluation, and diagnosis of B cell ALL/LBL and T cell ALL/LBL in children and adults are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

An overview of cytogenetic analysis in hematologic malignancies, including definitions, methods of detection, and genetic consequences of chromosomal translocations, is presented separately. (See "General aspects of cytogenetic analysis in hematologic malignancies".)

CYTOGENETIC AND MOLECULAR ABNORMALITIES — Most cases of ALL/LBL have recurring cytogenetic and/or molecular abnormalities that contribute to the phenotype, natural history, and/or prognosis of the disease. Notably, B cell ALL/LBL (B-ALL/LBL) and T cell ALL/LBL (T-ALL/LBL) have different characteristic, recurring cytogenetic and molecular features.

Cytogenetic features — Conventional karyotyping and fluorescence in situ hybridization (FISH) reveal recurring cytogenetic and/or molecular abnormalities in approximately 80 percent of cases of B-ALL/LBL and in 50 to 70 percent of T-ALL/LBL [1,2]. Individual cases may manifest numerical abnormalities (eg, hyperdiploidy, hypodiploidy), structural changes (eg, translocations, inversions, deletions), or both. Most chromosomal findings in ALL/LBL are associated with specific molecular/genetic abnormalities [3,4].

The frequency of certain chromosomal abnormalities varies considerably between childhood and adult B-ALL/LBL; it is uncertain if there are karyotypic differences in childhood and adult T-ALL/LBL. Examples of differences in age-related cytogenetic findings in B-ALL/LBL include [3,5-7]:

The t(9;22) is observed in 2 to 5 percent of children with ALL/LBL, compared with approximately one-third of adults .

The t(12;21) is present in approximately 25 percent of children with B-ALL/LBL, compared with about 3 percent of adults .

A hyperdiploid karyotype is found in 30 to 40 percent of children, compared with 2 to 10 percent of adults.

The t(4;11) is present in up to 60 percent of infants younger than 12 months but in <10 percent of adult ALL/LBL patients.

Molecular features — Genes that are important in the regulation of lymphocyte growth and development are frequently mutated in ALL/LBL. However, except for those associated with specific chromosomal findings in B-ALL/LBL, specific molecular abnormalities are not used to categorize ALL/LBL.

Mutations in genes encoding certain transcription factors (eg, MYC, IKZF1) or cell cycle regulators (eg, TP53, RB1, CDKN2A) are common, but they are generally associated with multiple World Health Organization (WHO) categories [1]. As an example, TP53 mutations were reported in 16 percent of B-ALL/LBL overall, but rates varied among disease categories (eg, the highest being 92 percent in B-ALL/LBL with low hypodiploidy) [6]. The frequency of TP53 abnormalities increased with age and was higher in B-ALL/LBL than in T-ALL/LBL (21 versus 8 percent, respectively). Abnormalities (eg, deletion, amplification, point mutation, or structural rearrangement) in PAX5 (32 percent), IKZF1 (28 percent), and other genes were reported in a study of 242 children with ALL/LBL [8]. In another study, genomic analysis in 1988 children and adults identified 23 subtypes of B-ALL/LBL on the basis of recurring chromosome translocations, unique gene fusions, mutations, and/or distinctive gene expression profiles; only some of these subtypes correspond to the current WHO categories [7].

Gene expression profiles, microRNA expression, and epigenetic changes appear to have prognostic value in patients with ALL/LBL [9-11]. However, with the exception of the distinctive gene expression profile of BCR-ABL1-like B cell ALL, these findings are not presently used to categorize ALL/LBL and their clinical value is not well-defined.

Gene mutations, rearrangements, and other molecular abnormalities that contribute to the pathogenesis of T-ALL/LBL are described in greater detail below. (See 'Non-TCR loci' below.)

WHO CLASSIFICATION OF ALL/LBL — The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues categorizes ALL/LBL according to lymphoid lineage, cytogenetic findings, and molecular features.

The 2016 WHO classification of ALL/LBL (table 1) is based on immunophenotype, cytogenetic abnormalities, and molecular findings [1,2]. ALL/LBL is broadly divided into tumors of B cell, T cell, and natural killer (NK) cell lineage, based on immunophenotype. In this system, cytogenetic and molecular features are relied on to subclassify B cell ALL/LBL (B-ALL/LBL), but not T cell ALL/LBL (T-ALL/LBL), early T cell precursor ALL/LBL, or NK cell ALL/LBL [1,2]. The WHO categories of ALL/LBL are presented in the sections that follow.

Details of the clinical evaluation, pathologic features, and diagnosis of ALL/LBL in children and adults are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

B-ALL/LBL — Most cases of B-ALL/LBL have a defining cytogenetic/molecular feature. Cytogenetic and molecular findings that are associated with phenotypic and/or prognostic features are fundamental to the WHO classification system (table 1) [1,2,12,13]. Cases that do not have one of the defining features should be classified as B-ALL/LBL, not otherwise specified (NOS). (See 'ALL/LBL, NOS' below.)

B-ALL/LBL with recurrent genetic abnormalities

t(9;22); BCR::ABL1 — The t(9;22)(q34.1;q11.2), called the Philadelphia (Ph) chromosome, generates the BCR::ABL1 fusion gene. The resultant BCR::ABL1 protein is a constitutively active tyrosine kinase, and this subtype of ALL/LBL is treated with chemotherapeutic regimens that incorporate a BCR::ABL1 tyrosine kinase inhibitor (TKI). The Ph chromosome is also seen in chronic myeloid leukemia (CML); clinical manifestations of CML and the biology and molecular genetics of BCR::ABL1 are discussed in detail separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Molecular genetics of chronic myeloid leukemia" and "Cellular and molecular biology of chronic myeloid leukemia".)

The t(9;22) is present in one-third of all adult cases of B-ALL/LBL and in half of adult cases in individuals >50 years; by contrast, only 5 percent of childhood B-ALL/LBL is BCR::ABL1 positive [3]. The clinical and morphologic features of t(9;22) are similar to other types of B-ALL/LBL. Although there may be organ involvement, purely lymphomatous presentations of B-ALL/LBL with t(9;22) are rare. The blasts in this subtype frequently express myeloid-associated markers, such as CD13 and CD33, and expression of CD25 is common in adults. Expression of both lymphoid and myeloid markers by this subtype may reflect transformation of a precursor cell that is less differentiated/more immature than other categories of ALL/LBL. In both adults and children, the presence of BCR::ABL1 is associated with adverse outcomes, but treatment regimens that include a TKI have greatly improved outcomes. The higher frequency of t(9;22) in adults may account, in part, for the overall adverse prognosis of B-ALL/LBL in this age group.

The t(9;22) creates a fusion of BCR at chromosome band 22q11.2 with ABL1 (which encodes a cytoplasmic tyrosine kinase) at 9q34.1. Approximately half of tumors in adults with B-ALL/LBL with t(9;22) produce a 210 kilodalton (kD) fusion protein (p210) and the remainder produce a p190 fusion protein; most tumors in children produce the p190 isoform [1]. The clinical behavior of tumors expressing p210 or p190 do not appear to differ.

In addition to the Ph chromosome, many cases of B-ALL/LBL with t(9;22) have additional cytogenetic abnormalities (ACAs). In a large series of adult B-ALL/LBL with t(9;22), approximately two-thirds had ACAs; gain of a Ph chromosome, -7, +8, +X, and del(9p) were the most common secondary abnormalities [14,15]. In the rare case when an additional subtype-defining cytogenetic finding is noted along with the t(9;22), the presence of t(9;22) appears to govern the clinical features of the disease and the disease should be subclassified as B-ALL/LBL with t(9;22). More than 80 percent of patients with B-ALL/LBL with t(9;22) have splicing abnormalities of IKZF1 (which encodes a zinc finger protein required for normal lymphoid development); certain IKZF1 isoforms may be associated with resistance to TKIs. However, abnormalities of IKZF1 are also found in other categories of B-ALL/LBL and they may be associated with poor outcomes, independent of Ph chromosome status [16,17]. As an example, a DNA copy number analysis of 221 patients with Ph chromosome-negative high-risk B-ALL/LBL and 258 unselected patients with B-ALL/LBL reported that patients with IKZF1 deletions had an increased frequency of relapse at 5 and 10 years and resistance to chemotherapy [18].

Management of B-ALL/LBL with the t(9;22) includes treatment with a TKI, as discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Remission induction therapy'.)

t(v;11q23.3) — The category of B-ALL/LBL with t(v;11q23.3) is the most common category of B-ALL/LBL in infants. It is defined by the presence of a translocation between KMT2A (also called MLL) at 11q23.3 and one of numerous fusion partners [1]. KMT2A is a histone methyltransferase that regulates gene transcription via chromatin remodeling; target genes include HOX genes and IKZF1, both of which have critical roles in normal lymphocyte development [19].

Translocations involving 11q23.3 are seen in 5 to 7 percent of all B-ALL/LBL cases, but in 60 to 80 percent of cases in infants (<1 year); it is less common in older children, but it again becomes slightly more common in adults [1,19]. Clinically, it typically presents with very high white blood cell (WBC) counts (eg, >100,000/microL) and frequent involvement of the central nervous system (CNS). Infant B-ALL/LBL with KMT2A translocations have a unique gene expression profile, suggesting that it constitutes a distinct disease entity. In a series of 1725 patients with pediatric B-ALL/LBL, children with tumors with KMT2A abnormalities had 50 and 60 percent five-year rates of event-free survival (EFS) and overall survival (OS), respectively, compared with 89 and 96 percent EFS and OS, respectively, in children with tumors belonging to the t(12;21) group [5].

There are no unique morphologic features that distinguish this category from other types of ALL/LBL. Leukemias with a deletion at 11q23.3 that do not have a KMT2A rearrangement are not included in this group. This category of B-ALL/LBL may show co-expression of myeloid and B cell markers and should be distinguished from leukemias that have distinct lymphoblastic and monoblastic populations (which can be confirmed by immunophenotyping); such cases should instead be classified as B/myeloid mixed phenotype leukemia (MPAL). (See "Mixed phenotype acute leukemia".)

Notable rearrangement partners for KMT2A include:

t(4;11) – The most common rearrangement is t(4;11)(q21.3;q23.3), which fuses KMT2A to AFF1 [19]. Patients characteristically have very high WBC counts, immature (progenitor B cell) immunophenotype (CD10-, CD19+, HLA-DR+), and co-expression of myeloid antigens (CD15+, CDw65+) [5,19]. Reverse transcriptase-polymerase chain reaction (RT-PCR) for the KMT2A-AFF1 transcript can be used for monitoring of measurable residual disease (MRD). (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

B-ALL/LBL with the t(4;11) has a poor prognosis in both adults and children. As examples, adults achieved a 75 percent complete remission (CR) rate, but median EFS was only seven months; for children, the rate of CR was 88 percent, but median survival was 10 months; for infants, five-year EFS was only 29 percent [5,7,8,20,21]. Among infants with KMT2A rearrangements, the t(4;11) may confer a particularly poor prognosis; as a result, intensified therapy, including transplantation, may be preferred in these patients [5].

t(11;19) – The second most common rearrangement is t(11;19)(q23.3;p13.3), which results in the KMT2A::MLLT1 (also called ENL) fusion, but approximately half of patients with this rearrangement have acute myeloid leukemia (AML; usually monoblastic). (See "Cytogenetic abnormalities in acute myeloid leukemia".)

t(12;21)(p13.2;q22.1); ETV6::RUNX1 — The t(12;21)(p13.2;q22.1) is the most common genetic lesion in childhood ALL/LBL. It occurs in 15 to 25 percent of childhood precursor B-ALL/LBL, but it is less common in adult disease (3 to 4 percent) [1].

There are no distinctive clinical, morphologic, or cytochemical features that distinguish t(12;21) from other types of ALL/LBL [1]. The t(12;21) is not easily detected by conventional karyotypic analysis because of the similarity in size and banding patterns of the 12p and 21q chromosome arms. As a result, fluorescence in situ hybridization (FISH) is generally required to detect this chromosomal rearrangement; its presence can also be inferred by using RT-PCR to detect the ETV6::RUNX1 fusion transcript.

Most patients with B-ALL/LBL with t(12;21) are 1 to 10 years old and have a favorable prognosis; >90 percent of patients are cured [1]. As examples, a study of 368 children with B-ALL/LBL reported that those with t(12;21) had 89 and 96 percent five-year EFS and OS, respectively, while another reported 91 percent five-year EFS [5,22].

The t(12;21) fuses ETV6 (TEL) at 12p13.2 with RUNX1 at 21q22.1, creating a chimeric gene that encodes ETV6::RUNX1 fusion protein [23]. Expression of ETV6::RUNX1 in marrow progenitor cells appears to induce a preleukemic stage of B-ALL/LBL development, but additional cooperating genetic mutations are required for the conversion into acute leukemia. The normal RUNX1 protein heterodimerizes with core binding factor beta (CBF beta) to form a functional transcription factor that regulates downstream target genes involved in numerous aspects of normal hematopoiesis. The t(12;21) fuses the region of ETV6 that encodes the 5' helix-loop-helix (HLH) dimerization domain with the region of RUNX1 that encodes the 3' DNA-binding and transactivation domain; the resulting fusion protein interferes with the transcriptional regulation of normal RUNX1 target genes. In many cases of B-ALL/LBL with the t(12;21), the ETV6 allele on the other chromosome 12 homolog is deleted, which suggests that ETV6 functions as a tumor suppressor gene. Germline mutations in ETV6 have been reported in association with germline predisposition to ALL [24].

ETV6 is also involved in other leukemias and myeloproliferative neoplasms. As an example, ETV6 is fused to the platelet-derived growth factor receptor (PDGFR)-beta gene in the t(5;12)(q32;p13.2), which is found in myeloid/lymphoid neoplasms with PDGFRB rearrangement (formerly classified as a subtype of chronic myelomonocytic leukemia) [1]. Two other recurring ETV6 fusions in myeloid neoplasms, ETV6::FLT3 in t(12;13) and ETV6::ABL1 in t(9;12), are recognized as additional causes of myeloid/lymphoid neoplasm with eosinophilia [20,25]. In addition ETV6::JAK2 and ETV6::NTRK3 fusions have been reported in BCR::ABL1 like B-ALL [26]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Myeloproliferative HES variants'.)

Aberrations involving RUNX1 are also found in other hematologic malignancies. These include RUNX1 translocations, most commonly the t(8;21)(q22;q22.1) in a genetically distinct subset of AML, and pathogenic somatic mutations in a subset of myelodysplastic syndrome and AML. In addition, germline RUNX1 mutations are the cause of familial platelet disorder with predisposition to AML, a rare autosomal dominant disorder associated with thrombocytopenia, platelet dysfunction leading to bleeding, and a high risk of myeloid neoplasia [27]. (See "Classification of acute myeloid leukemia (AML)", section on 'AML with t(8;21)(q22;q22); RUNX1-RUNX1T1' and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

Hyperdiploidy — B-ALL/LBL with hyperdiploidy is characterized by lymphoblasts that have >50 chromosomes and lack translocations or other structural alterations.

The clinical, morphologic, and cytochemical features of B-ALL/LBL with hyperdiploidy are similar to those of other categories [1]. Hyperdiploid B-ALL/LBL accounts for up to one-quarter of B-ALL/LBL in children; it is not seen in infants, the frequency decreases in older children, and it accounts for <10 percent of B-ALL/LBL in adults. Hyperdiploid ALL/LBL has a very favorable prognosis in children, with cure in >90 percent of children; there are too few adult cases to assess its prognostic significance. Children with hyperdiploid ALL typically have other favorable clinical features, such as age one to nine years, low WBC count, and favorable immunophenotype (early pre-B or pre-B) [5,11,28].

The X chromosome and chromosomes 21, 14, and 4 are most commonly gained in hyperdiploid B-ALL/LBL; chromosomes 1, 2, and 3 are least often gained. Hyperdiploid B-ALL/LBL with trisomies of chromosomes 4 and 10 have the most favorable prognosis. There is controversy about whether the features of hyperdiploid ALL/LBL are related to gain of particular chromosomes or the total number of chromosomes gained. As described below, rare cases of apparent "pseudohyperdiploid" ALL/LBL may stem from tetraploidization of hypodiploid ALL/LBL.

Hypodiploidy — Hypodiploid B-ALL/LBL has lymphoblasts with <46 chromosomes and is divided into subtypes based on the number of chromosomes; there may also be associated structural karyotypic abnormalities.

Three distinct subgroups of hypodiploid ALL/LBL have been identified, which have different genetic findings and prognoses [29,30]:

Near-haploid (23 to 29 chromosomes)

Low hypodiploid (33 to 39 chromosomes)

High hypodiploid (40 to 45 chromosomes)

There are no distinctive clinical, morphologic, or cytochemical features of this category. Hypodiploid B-ALL/LBL is uncommon, accounting for <5 percent of cases [31]. Although hypodiploid B-ALL/LBL occurs in both children and adults, the near-haploid category is limited to childhood. Importantly, the diagnosis of near-haploid or low hypodiploid B-ALL/LBL may be missed because the hypodiploid clone can undergo tetraploidization, which doubles the number of chromosomes, creating a near-diploid or hyperdiploid karyotype. Flow cytometric DNA index analysis or FISH assays to detect ploidy and copy number of selected chromosomes, and genomic microarray to detect allelic imbalances, such as loss of heterozygosity (LOH), can help clarify such ambiguous cases, which is important because of the distinctly different prognoses in these categories.

Subgroups of hypodiploid B-ALL/LBL are associated with distinctive genetic abnormalities [32]. Near-haploid B-ALL/LBL often has mutations of the RAS or PI3K signaling pathways, receptor tyrosine kinases, and/or IKZF3. The great majority of low hypodiploid cases have alterations of IKZF2, activation of RAS or PI3K signaling pathways, and/or loss-of-function mutations of RB1 and/or TP53 (some of which are germline). There are no specific gene alterations associated with high hypodiploid B-ALL/LBL.

Hypodiploid B-ALL/LBL generally carries a poor prognosis, especially in patients with near-haploid and low-hypodiploid clones. As an example, one study showed that the three-year EFS of children with near-haploid and low-hypodiploid clones was 29 percent, compared with 66 percent for those with high hypodiploid clones (42 to 45 chromosomes) [29].

t(5;14)(q31.1;q32.1); IGH/IL3 — The category of B-ALL/LBL with t(5;14)(q31.1;q32.1) is exceedingly rare in both children and adults. The translocation generates a fusion of IL3 and an IGH (immunoglobulin heavy chain) that causes overexpression of IL3 and is associated with variable degrees of eosinophilia.

The clinical features can resemble other types of B-ALL/LBL, but some cases present with asymptomatic eosinophilia and few blasts in peripheral blood [1]. The blasts have typical ALL/LBL morphology, but there may be an increase of eosinophils, which are not part of the leukemic clone (ie, they constitute a reactive population of eosinophils). There are too few reported cases to be certain of the prognosis of this subtype.

t(1;19)(q23;p13.3)/TCF3::PBX1 — The category of B-ALL/LBL with t(1;19)(q23;p13.3)/TCF3::PBX1 has blasts that harbor a translocation between TCF3 (E2A) on chromosome 19 and PBX1 on chromosome 1.

This category is relatively common in children (6 percent) and less common in adults [1]. The morphologic and cytochemical features are similar to those of other categories of ALL/LBL. The blasts have a pre-B phenotype (ie, positive for CD19, CD10, and cytoplasmic mu heavy chain), and this rearrangement accounts for approximately one-third of cases of childhood pre-B cell ALL/LBL. Clinically, there is an increased risk for CNS relapse. Although the t(1;19) rearrangement was formerly considered to carry a poor prognosis, outcomes using contemporary intensive therapy are now comparable or more favorable than other categories of ALL/LBL [5].

This rearrangement creates a chimeric gene encoding a TCF3::PBX1 fusion protein, which contains the transcriptional activation domain of TCF3 and the DNA-binding and protein dimerization domains of PBX1 (a homeobox [HOX] protein). This fusion protein appears to interfere with functions of wild-type TCF3 and PBX1. The functional fusion gene is present on chromosome 19; in some cases, there is an unbalanced translocation with loss of the derivative chromosome 1. B-ALL/LBL with t(1;19) has a unique gene expression signature [33].

Some cases of B-ALL/LBL with a t(1;19) do not involve either TCF3 or PBX1; such cases should not be included in this category. Demonstration of a TCF3 rearrangement alone is not sufficient to establish the presence of the t(1;19), as rare cases of B-ALL/LBL have a t(17;19) in which TCF3 is translocated to HLF on chromosome 17; such cases are associated with a dismal prognosis.

iAMP21 — B-ALL/LBL with iAMP21 is a provisional category in the WHO classification in which blasts have amplification of a portion of chromosome 21 [1].

This category accounts for 2 percent of cases of B-ALL/LBL and is usually found in older children who present with low WBC counts [1]. There are no distinctive morphologic and cytochemical features. It is usually detected by FISH with a probe for RUNX1 that reveals ≥5 copies of the gene or ≥3 extra copies on a single abnormal chromosome. Individuals with the rare constitutional Robertsonian translocation rob(15;21)(q10;q10)c have a nearly 3000-fold increased risk of developing this type of ALL/LBL [34]. ALL/LBL with iAMP21 has been considered to carry a poor prognosis, although this is less clear in the era of intensified therapy [35].

Various structural abnormalities of 21q are found by cytogenetic analysis, including an increase in the length of 21q, consistent with gene amplification [35]. Genomic microarray studies revealed complex genomic imbalances of 21q, with multiple gains of most of the long arm of the chromosome, along with deletion of the subtelomeric region [36]. Detailed analysis revealed that breakage-fusion-bridge cycles occurred first, followed by chromothripsis, leading to the formation of tandem duplications of 21q [34]. Even though RUNX1 is part of the consistently amplified critical region of chromosome 21, RUNX1 translocations or mutations are not observed and the pathogenesis does not appear to involve RUNX1. In one-fifth of cases, iAMP21 is the only cytogenetic abnormality, but in other cases there are other karyotypic or molecular findings, including gains of the X chromosome, abnormalities of chromosome 7, del(9p), del(12p), del(13q)/RB1, deletion of IKZF1, P2YB8::CRLF2 fusion, rearrangements of CRLF2, and deletions of RB1 and ETV6; it remains uncertain if these additional changes contribute to the pathogenesis of this leukemia [35]. Cases that include iAMP21 plus another genetic lesion that might suggest another category (eg, CRLF2 translocation) should be classified as ALL/LBL with iAMP21.

BCR::ABL1-like B cell ALL — BCR::ABL1-like B cell ALL is a provisional category in the 2016 WHO classification that shares a similar gene expression profile with B-ALL/LBL with t(9;22)/BCR::ABL1, but lacks the BCR::ABL1 fusion or t(9;22) by cytogenetic, FISH, or molecular analysis [1,2,9]. This category is found in 10 to 13 percent of pediatric patients, 21 percent of adolescents, and up to 33 percent of adults with B-ALL/LBL; it is resistant to standard chemotherapy and associated with a poor prognosis [16,21,22,37-40]. BCR::ABL1-like B-ALL/LBL is mutually exclusive of other well-defined recurring chromosome abnormalities in B-ALL/LBL, such as the t(12;21), t(4;11) and other 11q23.3/KMT2A translocations, t(1;19), and a hyperdiploid karyotype.

The diagnosis can be made using RNA sequencing-based methods that directly detect fusion transcripts [21]. It can often be inferred by flow cytometry (eg, expression of CRLF2), conventional karyotype, FISH (eg, rearrangement of frequently involved genes), and/or mutation and deletion analysis [40]. Detection of BCR::ABL1-like B cell ALL is important for prognosis and treatment stratification. Compared with other cases of precursor B cell ALL, this subgroup has higher WBC count at presentation, higher levels of MRD at the end of induction therapy, and inferior five-year EFS and OS.

In a study of 798 adult patients with B-ALL, BCR::ABL1-like ALL was reported in 28 percent of patients age 21 to 39, 20 percent of patients 40 to 59 years, and 24 percent of those age 60 to 89 [21]. In a study of 1725 children, adolescents, or young adults with precursor B cell ALL enrolled on clinical trials, BCR::ABL1-like ALL was found in 15 percent [37,39]. Another study reported BCR::ABL1-like ALL in 20 percent of nearly 1400 consecutively diagnosed patients with childhood B-ALL enrolled in Children's Oncology Group trials [41].

Genes that are mutated in BCR::ABL1-like B-ALL generally encode proteins involved in B cell development, proliferation and differentiation, cell cycle regulation, and cell signaling. These mutations result in constitutive kinase activation and signaling via activation of the ABL1 and JAK-STAT pathways, which are sensitive to TKIs or JAK kinase inhibitors [37,41,42]. Genetic findings include ABL1-class fusions; rearrangements of EPOR, JAK2, or CRLF2; and other changes that affect genes encoding components of the JAK/STAT or RAS pathways [21,22,37,39,41,42].

In approximately half of patients with the BCR::ABL1-like B cell ALL, the cytokine receptor-like factor 2 (CRLF2) gene within the pseudo-autosomal region 1 (PAR1) of the short arm of the X or Y chromosome is involved in a cryptic translocation with the IGH gene at 14q32.3 (ie, t(X;14) or t(Y;14)), or is fused with the P2RY8 gene via small interstitial deletions within PAR1 [16,37]. Both chromosome translocations and the interstitial deletion lead to CRLF2 overexpression due to juxtaposition with the IGH enhancer or the P2RY8 promoter. Rarely, gain-of-function point mutations of the CRLF2 gene or gain of extra copies of the CRLF2 locus can result in its overexpression. In approximately 30 to 55 percent of these patients, mutations in JAK2 or JAK1 or in IL7R, FLT3, SH2B3, or NRAS are also detected, indicative of the cooperation of these kinase-activating lesions with CRLF2 overexpression in leukemogenesis [37,38]. In addition, deletion of part or all of IKZF1, PAX5, and EBF1 are frequently detected in these leukemias. In almost all patients with Down syndrome-related B cell ALL, the blasts have a deletion of IKZF1 [38].

In the remaining BCR::ABL1-like B cell ALL cases with no CRLF2 overexpression, other tyrosine kinase genes, such as ABL1, ABL2, JAK2, EPOR, and PDGFRB, are involved by translocations and fusions that produce chimeric genes encoding constitutively active kinases; these include NUP214::ABL1, BCR::JAK2, STRB3::JAK2, IGH::EPOR, EBF1::PDGFRB, and AGGF1::PDGFRB fusions [37,39,43]. In addition, mutations of FLT3, CREBBP, IL7R, or SH2B3 (LNK) occur frequently in these patients.

ALL/LBL, NOS — B-ALL/LBL, not otherwise specified (NOS) includes cases with chromosomal abnormalities that are not known to be associated with phenotypic or prognostic distinctions. Chromosomal abnormalities that are not clearly associated with phenotypic or prognostic distinctions include del(6q), del(9q), and del (12p). Other cases of B-ALL/LBL, NOS have sub-karyotypic abnormalities or novel fusion genes, without associated chromosomal abnormalities.

Chromosome 9p abnormalities — Abnormalities of the short arm of chromosome 9 are found in approximately 5 to 10 percent of childhood and adult ALL cases [1]. This can occur as a single abnormality in childhood and adult disease, but it often exists as a part of a complex clone with other numerical and structural abnormalities, in particular with a del(12p). Abnormalities involving 9p include del(9p), add(9p), der(9)t(V;9)(V;p), isochromosome 9q, and dicentric chromosome 9q.

Deletion of 9p is an unfavorable risk factor and is associated with a high rate of relapse in precursor B cell ALL in children [44]. Abnormalities in 9p were reported in 8 percent of 381 adult cases of precursor B cell ALL; OS was decreased compared with patients with normal karyotypes and was similar to those with poor prognosis t(9;22)/BCR::ABL1-positive ALL [45].

The pathophysiology of 9p abnormalities is unclear. In one study, monoallelic deletion of the PAX5 gene at 9p13.2 was seen by microarray analysis and genomic DNA sequencing in 28 percent of patients with a cryptic or a large deletion involving chromosome 9 [8]. Deletion or mutation of PAX5 leads to loss-of-function by reducing PAX5 protein levels or creating a hypomorphic allele [46]. Somatically acquired mutations in JAK2 on 9p24 were reported in 18 percent of cases of Down syndrome-associated B-ALL/LBL, but are not commonly found in B-ALL/LBL without Down syndrome or in Down syndrome-associated acute megakaryoblastic leukemia [47-49]. The JAK2 R683 mutation in this setting differs from the JAK2 V617 mutation associated with myeloproliferative neoplasms.

Other recurring gene fusions — Up to 30 percent of B-ALL/LBL cases are not defined by current WHO genetic subgroups (ie, they do not have recurring chromosome abnormalities, kinase activating gene fusions, or Ph-like B-ALL). Next-generation sequencing of RNA and other genomic studies have revealed several recurring genetic abnormalities in this category of B-ALL/LBL, especially in adolescent and young adult patients. Examples include:

MEF2D::BCL9 fusion – The myocyte enhancer factor 2D (MEF2D) gene encodes a transcription factor that participates in neuronal development and myogenesis. Fusion of MEF2D with BCL9 or other genes was detected in 5 to 7 percent of B-ALL/LBL, mostly in cases occurring in adolescents [50,51]. B-ALL/LBL with the MEF2D::BCL9 fusion is characterized by a distinct immunophenotype, similar to that of B-ALL/LBL with the t(1;19), markedly high expression of HDAC9, resistance to chemotherapy, early relapse, and a poor outcome.

DUX4::ERG or DUX4::IGH fusion – The double homeobox 4 gene (DUX4) is located near the telomere of the long arm of chromosome 4 and encodes the transcriptional activator PITX1. DUX4-IGH or DUX4-ERG fusions were detected in about 4 to 7 percent of B-ALL/LBL in pediatric and young patients [52-55]. The DUX4-IGH translocation leads to overexpression of an altered DUX4 protein with an aberrant carboxy terminus that induces B cell leukemia in mice. Nearly all patients with DUX4 aberrations also show deletion of ERG, indicative of the cooperation of DUX4 and ERG in mediating leukemogenesis.

EP300::ZNF384 and CREBBP::ZNF384 fusions – The zinc finger protein ZNF384 regulates expression of genes encoding extracellular matrix proteins. An EP300::ZNF384 or CREBBP::ZNF384 fusion is detected in 7 to 12 percent of B-ALL/LBL in adolescent and young adult patients; the disease is CD10-negative and is characterized by high expression of GATA3, CEBPA, and CEBPB, upregulated JAK-STAT signaling, and a relatively low frequency of mutations or deletions of B cell development-related genes, such as IKZF1, PAX5, RUNX1, ETV6, or the cell cycle regulators CDKN2A/CDKN2B [55,56].

UBTF::ATXN7L3 fusion and CDX2 overexpression: B-ALL/LBL with UBTF::ATXN7L3 fusion and CDX2 overexpression are high-risk subgroups with unique biological features that are mostly seen in adolescent and young adult females.

These abnormalities can be detected in about 1 to 2 percent of B-ALL/LBL, mostly in adolescent and adult female patients with median age of 31-35 years [57-60]. Aberrant CDX2 activation was seen in 17 of 3221 cases of primary B-ALL/LBL and in 5 of 177 cases of relapsed B-ALL/LBL among (among 177 cases) [57]. CDX2 activation stems from a focal deletion downstream of PAN3 at 13q12.2 that hijacks the PAN3 enhancer. The UBTF::ATXN7L3 fusion results from a microdeletion of about 10 kb involving exon 18-21 of UBTF at 17q21.31 [58]. This form of B-ALL/LBL generally lacks CD10 expression and is often IgM positive. Patients in these groups often have high-risk features, including high relapse rates and high residual disease burden at the end on intensive induction treatment.

Burkitt lymphoma/leukemia — The t(8;14)(q24.2;q32.3) reciprocal translocation, resulting in constitutive expression of the MYC gene as a result of the IGH::MYC translocation, is present in a high proportion of Burkitt lymphoma/leukemia of both African and non-African origin. Burkitt lymphoma/leukemia is derived from transformed germinal center B cells, and in the 2016 revision of the WHO classification system (table 1) is classified together with other non-Hodgkin lymphomas of B cell origin. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

T-ALL/LBL — T cell ALL/LBL (T-ALL/LBL) is a hematologic malignancy of precursor lymphoid cells committed to the T cell lineage. T-ALL/LBL accounts for approximately 15 percent of childhood ALL/LBL; it is more common in adolescents than in younger children, and more common in boys than in girls [1]. It accounts for one-quarter of adult cases of ALL/LBL. Importantly, T-ALL/LBL accounts for 85 to 90 percent of lymphoblastic lymphoma presentations. Clinical manifestations, pathologic features, and diagnosis of T-ALL/LBL are described separately. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Cytogenetic abnormalities in T-ALL/LBL — An abnormal karyotype is found in 50 to 70 percent of cases of T-ALL/LBL. However, in many cases, rearrangements are not detected by karyotyping but are only recognized by molecular genetic studies. As an example, rearrangements involving TAL1 are present in 20 to 30 percent of cases of T-ALL/LBL, but a cytogenetic finding of t(1;14)(p33;q11.2) is detected in only 3 percent; in many cases, TAL1 is fused to STIL as a result of a cryptic interstitial deletion at chromosome band 1p33. In contrast to the important prognostic impact of recurring cytogenetic abnormalities in B cell ALL/LBL, the prognostic implication of chromosomal translocations and gene mutations and fusions, described below, is less well-defined in T-ALL/LBL.

Molecular abnormalities in T-ALL/LBL

TCR rearrangements — The most common recurrent molecular/genetic abnormalities in T-ALL/LBL involve rearrangements of the TCR (T cell receptor) alpha and delta loci at 14q11.2, beta locus at 7q34, and gamma locus at 7p14.1 with various partner genes [61-63]. Most partner genes encode a transcription factor or cell cycle regulator whose expression is dysregulated or activated by juxtaposition to transcriptional regulatory elements of the TCR loci. TLX1 (HOX11) at 10q24.3 is the partner in 7 percent of childhood and 30 percent of adult cases; TLX3 (HOX11L2) at 5q35.1 is rearranged in 20 percent of childhood and 10 to 15 percent of adult cases. Other partner genes include MYC at 8q24.2, TAL1 at 1p33, LMO1 (RBTN1) at 11p15.4, LMO2 (RBTN2) at 11p13, LYL1 at 19p13.1, and the tyrosine kinase LCK at 1p35.2.

Non-TCR loci — Other karyotypic and/or mutational abnormalities in T-ALL/LBL that do not involve the TCR loci, include [1,61,64-68]:

t(10;11)(p12.2;q14.2), which generates the PICALM-MLLT10 fusion; 10 percent of cases.

KMT2A translocations, often with the MLLT1 (ENL) partner gene at 19p13.1; 8 percent of cases.

del(9p), which in 30 percent of cases is associated with loss of expression of CDKN2A and CDKN2B, which encode p16 and p15 (inhibitors of CDK4/6) as well as ARF (also known as p14), a protein that stabilizes p53.

NOTCH1 activating mutations, generally producing changes in the amino acid sequence of the extracellular heterodimerization domain and/or truncations of the C-terminal PEST domain; approximately half of cases.

JAK1 or JAK3 mutations.

NUP214::ABL1 cryptic fusion (ie, not detectable by conventional chromosome analysis) is present in approximately 6 percent of T-ALL/LBL (and rare cases of B-ALL/LBL); it is detectable by fluorescence in situ hybridization (FISH) as episomal amplicons with variable numbers of copies of ABL1 or as a homogeneous staining region (HSR).

Disorders that affect regulators of T cell growth and development contribute to T-ALL/LBL leukemogenesis. It has been proposed that there are four functionally distinct subgroups of T-ALL/LBL, based on specific translocations that lead to aberrant expression of 1) TAL1 or LMO1/LMO2, 2) TLX1, 3) TLX3, or 4) HOXA genes, all of which cause T cell maturation arrest at distinct stages of thymocyte development [69,70]. PICALM::MLLT10 and KMT2A::MLLT1 activate HOXA genes; MYC, which contributes to growth of the malignant cells, is a direct downstream target of NOTCH1; and mutations of FBXW7 increase the half-life of the NOTCH1 protein [71,72]. The NUP214::ABL1 fusion is often associated with abnormalities of TLX1 or TLX3, and other recurring genetic aberrations in T-ALL/LBL, such as deletions of CDKN2A, CDKN2B, and IKZF1.

Several mechanisms have been proposed to explain the higher incidence of T-ALL/LBL in males. Recurrent mutations of loci on the X chromosome may contribute to the sex predilection. As an example, inactivating mutations or deletions in the PHF6 locus on the X chromosome are found in 16 percent and 38 percent of primary T cell ALL/LBL in children and adults, respectively; loss of PHF6 is associated with aberrant expression of TLX1 [73]. Similarly, a small percentage of cases demonstrate mutations in the ribosomal gene RPL10 located on the X chromosome [74]. However, mutations of these loci seemingly cannot account for the difference in incidence between males and females because they are located in regions that undergo X inactivation in females. Some of the sex predilection may be explained by mutations in UTX (KDM6A), a tumor suppressor located in a region of the X chromosome that escapes X inactivation in females [75,76]. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma", section on 'Epidemiology'.)

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the expression of genes at the post-transcriptional level and may have particular relevance in T-ALL. Expression profiles in human T-ALL have identified a small number of abundantly expressed miRNAs that target a set of tumor suppressor genes (IKZF1, PTEN, BIM, NF1, FBXW7, and PHF) and promote T-ALL in mice [77]. As an example, mir-223 is differentially upregulated in T-ALL/LBL and appears to promote NOTCH1-driven leukemia.

EARLY T CELL PRECURSOR ALL/LBL — Early T cell precursor (ETP)-ALL/LBL is a hematologic malignancy of cells committed to the T cell lineage but with a unique immunophenotype corresponding to very early stages of T cell differentiation [1].

ETP-ALL cells lack expression of CD1a and CD8 and have weak expression of CD5 [78]. These cases account for up to 15 percent of T-ALL/LBL in children and 5 to 10 percent in adults and are generally associated with a higher rate of treatment failure. Whole genome sequencing of tumor cells from 12 pediatric patients with ETP-ALL/LBL demonstrated a high frequency of somatic mutations involving the pathways of normal hematopoietic development, RAS signaling, and histone modification that are similar to those commonly involved in acute myeloid leukemia [79]. This study also failed to detect mutations in NOTCH1, the gene that is most commonly mutated in T-ALL/LBL in both children and adults. However, a subsequent study of 68 adult cases of ETP-ALL/LBL identified NOTCH1 mutations in approximately 15 percent of cases, along with several other mutations that are more characteristic of acute myeloid leukemia, such as mutations in DNMT3A and FLT3 [80].

Acute leukemia with BCL11B rearrangements has been identified as an entity among ETP-ALL and mixed lineage acute leukemia (MPAL); abnormalities include translocations, insertions, or focal tandem duplications/amplifications) [81,82]. Whole genome sequencing detected several BCL11B-related rearrangements, including t(2;14), t(3;14), t(6;14), t(7;14), t(8;14), t(12;14) and t(14;21). These rearrangements involve diverse fusion partners, specifically ZEB2 at 2q22.3, SATB1 at 3p24.3, ARID1 at 6q25.3, CDK6 at 7q22.1, CCDC26/MYC at 8q24.2, ETV6 at 12p13.2, and RUNX1 at 21q22.1. All appear to relocate super-enhancers to positions near the BCL11B gene at 14q32.2, leading to increased BCL11B expression. The BCL11B protein is a critical transcription factor in regulating thymic T lineage commitment and specification, and its overexpression leads to the inhibition of the T cell differentiation and activation of the JAK/STAT transduction pathway.

NK CELL ALL/LBL — Natural killer (NK) cell ALL/LBL is a provisional category of ALL/LBL in the 2016 World Health Organization classification [1]. This is a rare entity that must be distinguished from blastic plasmacytoid dendritic cell neoplasms (BPDCN), myeloid/NK acute leukemia, and other malignancies that express NK cell markers, such as CD56 [1]. Chromosomal and genetic abnormalities of NK cell ALL/LBL are not defined.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY

Description – Acute lymphoblastic leukemia/lymphoma (ALL/LBL) refers to hematologic malignancies of lymphoid precursor cells. These entities are described as ALL/LBL because leukemia and lymphoma are overlapping clinical presentations of these diseases; diagnosis and classification systems do not distinguish between leukemia and lymphoma. (See 'Introduction' above.)

Broadly, ALL/LBL is divided into B cell and T cell lineages; rare cases are associated with the natural killer (NK) cell lineage. Immunophenotyping is required to determine the lineage of ALL/LBL because the various lineages are morphologically indistinguishable.

Cytogenetic and molecular abnormalities in ALL/LBL – Conventional karyotyping and fluorescence in situ hybridization (FISH) reveal recurring cytogenetic and/or molecular abnormalities in most cases of ALL/LBL. Many of these findings contribute to the disease phenotype, natural history, and/or prognosis. Characteristic cytogenetic and molecular features differ between B cell ALL/LBL (B-ALL/LBL) and T cell ALL/LBL (T-ALL/LBL). (See 'Cytogenetic and molecular abnormalities' above.)

Genetic features and classification of ALL/LBL – In the World Health Organization (WHO) classification system of hematologic malignancies (table 1), cytogenetic and molecular features are fundamental to categorizing B-ALL/LBL; such features are not used to classify T-ALL/LBL, early T cell precursor ALL/LBL, or NK cell ALL/LBL. (See 'WHO classification of ALL/LBL' above.)

B-ALL/LBL – The various WHO categories of B-ALL/LBL with recurrent genetic abnormalities are described above. (See 'B-ALL/LBL with recurrent genetic abnormalities' above.)

B-ALL/LBL that does not include one of the specified recurrent genetic abnormalities is categorized as B-ALL/LBL, not otherwise specified (NOS). (See 'ALL/LBL, NOS' above.)

T-ALL/LBL – Cytogenetic and molecular features of T-ALL/LBL are described above. (See 'T-ALL/LBL' above.)

Other ALL/LBL categories – Cytogenetic and molecular features are not well-defined for other WHO-defined categories of ALL/LBL. (See 'Early T cell precursor ALL/LBL' above and 'NK cell ALL/LBL' above.)

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Topic 4484 Version 43.0

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