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Childhood Cancer Genomics (PDQ®): Treatment - Health Professional Information [NCI]

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General Information About Childhood Cancer Genomics

Research teams from around the world have made remarkable progress in the past decade in elucidating the genomic landscape of most types of childhood cancer. A decade ago it was possible to hope that targetable oncogenes, such as activated tyrosine kinases, might be identified in a high percentage of childhood cancers. However, it is now clear that the genomic landscape of childhood cancer is highly varied, and in many cases is quite distinctive from that of the common adult cancers.

There are examples of genomic lesions that have provided immediate therapeutic direction, including the following:

  • NPM-ALK fusion genes associated with anaplastic large cell lymphoma cases.
  • ALK point mutations associated with a subset of neuroblastoma cases.
  • BRAF and other kinase genomic alterations associated with subsets of pediatric glioma cases.
  • Hedgehog pathway mutations associated with a subset of medulloblastoma cases.
  • ABL family genes activated by translocation in a subset of acute lymphoblastic leukemia (ALL) cases.

For some cancers, the genomic findings have been highly illuminating in the identification of genomically defined subsets of patients within histologies that have distinctive biological features and distinctive clinical characteristics (particularly in terms of prognosis). In some instances, identification of these subtypes has resulted in early clinical translation as exemplified by the WNT subgroup of medulloblastoma. Because of its excellent outcome, the WNT subgroup will be studied separately in future medulloblastoma clinical trials so that reductions in therapy can be evaluated with the goal of maintaining favorable outcome while reducing long-term morbidity. However, the prognostic significance of the recurring genomic lesions for some other cancers remains to be defined.

A key finding from genomic studies is the extent to which the molecular characteristics of childhood cancers correlate with their tissue (cell) of origin. As with most adult cancers, mutations in childhood cancers do not arise at random, but rather are linked in specific constellations to disease categories. A few examples include the following:

  • The presence of H3.3 and H3.1 K27 mutations almost exclusively among pediatric midline high-grade gliomas.
  • The loss of SMARCB1 in rhabdoid tumors.
  • The presence of RELA translocations in supratentorial ependymomas.
  • The presence of specific fusion proteins in different pediatric sarcomas.

Another theme across multiple childhood cancers is the contribution of mutations of genes involved in normal development of the tissue of origin of the cancer and the contribution of genes involved in epigenomic regulation.

Structural variations play an important role for many childhood cancers. Translocations resulting in oncogenic fusion genes or overexpression of oncogenes play a central role, particularly for the leukemias and sarcomas. However, for other childhood cancers that are primarily characterized by structural variations, functional fusion genes are not produced. Mechanisms by which these recurring structural variations have oncogenic effects have been identified for osteosarcoma (translocations confined to the first intron of TP53) and medulloblastoma (structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements leading to transcriptional activation [enhancer hijacking]).[1,2] However, the oncogenic mechanisms of action for recurring structural variations of other childhood cancers (e.g., the segmental chromosomal alterations in neuroblastoma) need to be elucidated.

Understanding of the contribution of germline mutations to childhood cancer etiology is being advanced by the application of whole-genome and exome sequencing to cohorts of children with cancer. Estimates for rates of pathogenic germline mutations approaching 10% have emerged from studies applying these sequencing methods to childhood cancer cohorts.[3,4,5] In some cases, the pathogenic germline mutations are clearly contributory to the patient's cancer (e.g., TP53 mutations arising in the context of Li-Fraumeni syndrome), whereas in other cases the contribution of the germline mutation to the patient's cancer is less clear (e.g., mutations in adult cancer predisposition genes such as BRCA1 and BRCA2 that have an undefined role in childhood cancer predisposition).[4,5] The frequency of germline mutations varies by tumor type (e.g., lower for neuroblastoma and higher for osteosarcoma),[5] and many of the identified germline mutations fit into known predisposition syndromes (e.g., DICER1 for pleuropulmonary blastoma, SMARCB1 and SMARCA4 for rhabdoid tumor and small cell ovarian cancer, TP53 for adrenocortical carcinoma and Li-Fraumeni syndrome cancers, RB1 for retinoblastoma, etc.). The germline contribution to the development of specific cancers is discussed in the disease-specific sections that follow.

Each section of this document is meant to provide readers with a brief summary of current knowledge about the genomic landscape of specific childhood cancers, an understanding that is critical in considering how to apply precision medicine concepts to childhood cancers.


  1. Northcott PA, Lee C, Zichner T, et al.: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511 (7510): 428-34, 2014.
  2. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014.
  3. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015.
  4. Parsons DW, Roy A, Yang Y, et al.: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. JAMA Oncol : , 2016.
  5. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015.


Acute Lymphoblastic Leukemia (ALL)

The genomics of childhood ALL has been extensively investigated and multiple distinctive subtypes based on cytogenetic and molecular characterizations have been defined, each with its own pattern of clinical and prognostic characteristics.[1]Figure 1 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.[1]Pie chart showing subclassification of childhood ALL.
Figure 1. Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL. Reprinted from Seminars in Hematology, Volume 50, Charles G. Mullighan, Genomic Characterization of Childhood Acute Lymphoblastic Leukemia, Pages 314–324, Copyright (2013), with permission from Elsevier.

The genomic landscape of B-precursor ALL is typified by a range of genomic alterations that disrupt normal B-cell development and in some cases by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3-PBX1 and ETV6-RUNX1), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[2]

The genomic alterations in B-precursor ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3-PBX1 and ETV6-RUNX1, and MLL (KMT2A)-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:

  • IKZF1 deletions and mutations are most commonly observed within cases of Philadelphia chromosome–positive (Ph+) ALL and Ph-like ALL.[3,4]
  • Intragenic ERG deletions occur within a distinctive subtype characterized by this alteration and lacking other recurring cytogenetic alterations associated with pediatric B-precursor ALL.[5,6,7]
  • TP53 mutations occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes, and the TP53 mutations in these patients are often germline.[8]TP53 mutations are uncommon in other patients with B-precursor ALL.

Activating point mutations in kinase genes are uncommon in high-risk B-precursor ALL, and JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome ALL.[4,9,10] Several kinase genes and cytokine receptor genes are activated by translocation as described below in the discussion of Ph-positive ALL and Ph-like ALL. FLT3 mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and MLL (KMT2A)-rearranged ALL, and are rare in other subtypes.[11]

Understanding of the genomics of B-precursor ALL at relapse is less advanced than understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[12] Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-precursor ALL with early relapse that were evaluated for this mutation.[12,13]NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to 6-mercaptopurine and thioguanine.[13] Another gene that is found mutated only at relapse is PRSP1, a gene involved purine biosynthesis.[14] Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[12,15] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.

Specific genomic and chromosomal alterations are provided below, with a focus on their prognostic significance.

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in precursor B-cell ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)(q34;q11.2)), rearrangements of the MLL (KMT2A) gene, hypodiploidy, and intrachromosomal amplification of the AML1 gene (iAMP21).[16]

In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for precursor B-cell ALL:[17]

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

  1. Chromosome number
    • High hyperdiploidy (51–65 chromosomes)

      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL.[18] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is itself an independent favorable prognostic factor.[18,19,20] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[20] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[21] which may explain the favorable outcome commonly observed in these cases.

      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[22,23]

      Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group analyses of National Cancer Institute (NCI) standard-risk ALL.[24] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[25]

      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)(q34;q11.2)) also had high hyperdiploidy,[26] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive (Ph+) high hyperdiploid patients.

      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[27] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.[27]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[28] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[28,29,30] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[28,30]

      The genomic landscape of hyperdiploid ALL is represented by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL.[31]

    • Hypodiploidy (<44 chromosomes)

      Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:[27]

      • Near-haploid: 24 to 29 chromosomes (n = 46).
      • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
      • High-hypodiploid: 40 to 43 chromosomes (n = 13).
      • Near-diploid: 44 chromosomes (n = 54).

      Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[27,32] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[27] One study of 20 patients with near-haploid or low-hypodiploid ALL indicated that MRD may have prognostic significance in the hypodiploid population.[33]

      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[34] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8]

  2. Chromosomal translocations and gains/deletions of chromosomal segments
    • t(12;21)(p13.2;q22.1); ETV6-RUNX1 (formerly known as TEL-AML1)

      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in 20% to 25% of cases of precursor B-cell ALL but is rarely observed in T-cell ALL.[29] The t(12;21)(p12;q22) produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[35,36] Hispanic children with ALL have a lower incidence of t(12;21)(p13;q22) than do white children.[37]

      Reports generally indicate favorable event-free survival (EFS) and overall survival (OS) in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[38,39,40,41,42]

      • Early response to treatment.
      • NCI risk category (age and WBC count at diagnosis).
      • Treatment regimen.

      In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors.[38] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion.[42,43] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other precursor B-cell ALL.[38,44] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[45] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[46] Some relapses in patients with t(12;21)(p13;q22) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[47,48]

    • t(9;22)(q34.1;q11.2); BCR-ABL1 (Ph+)

      The Philadelphia chromosome t(9;22)(q34;q11.2) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (refer to Figure 2). Philadelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the abl gene and a normal chromosome 22 with the bcr gene. In the center panel, the drawing shows chromosome 9 breaking apart in the abl gene and chromosome 22 breaking apart below the bcr gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached and chromosome 22 with the piece from chromosome 9 containing part of the abl gene attached. The changed chromosome 22 with bcr-abl gene is called the Philadelphia chromosome.
      Figure 2. The Philadelphia chromosome is a translocation between the ABL-1 oncogene (on the long arm of chromosome 9) and the breakpoint cluster region (BCR) (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL1 encodes an oncogenic protein with tyrosine kinase activity.

      This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count, with the incidence of the t(9;22)(q34;q11.2) increasing to about 25% in young adults with ALL.

      Historically, the Philadelphia chromosome t(9;22)(q34;q11.2) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[26,49,50,51] Inhibitors of the BCR-ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[52] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[53,54]

    • t(v;11q23.3); MLL (KMT2A)-rearranged

      Rearrangements involving the MLL (KMT2A) gene occur in approximately 5% of childhood ALL cases overall, but in up to 80% of infants with ALL. These rearrangements are generally associated with an increased risk of treatment failure.[55,56,57,58] The t(4;11)(q21;q23) is the most common rearrangement involving the MLL gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[56,59]

      Patients with the t(4;11)(q21;q23) are usually infants with high WBC counts; they are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[60] While both infants and adults with the t(4;11)(q21;q23) are at high risk of treatment failure, children with the t(4;11)(q21;q23) appear to have a better outcome than either infants or adults.[55,56] Irrespective of the type of MLL (KMT2A) gene rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have an MLL gene rearrangement.[55,56] Whole-genome sequencing has determined that cases of infant ALL with MLL gene rearrangements have few additional genomic alterations, none of which have clear clinical significance.[11] Deletion of the MLL gene has not been associated with an adverse prognosis.[61]

      Of interest, the t(11;19)(q23;p13.3) involving MLL (KMT2A) and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL.[62] Outcome for infants with the t(11;19) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19).[62]

    • t(1;19)(q23;p13.3); TCF3-PBX1 and t(17;19)(q22;p13); TCF3-HLF

      The t(1;19) occurs in approximately 5% of childhood ALL cases and involves fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1.[63,64] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B ALL immunophenotype (cytoplasmic Ig positive).[65] Black children are relatively more likely than white children to have pre-B ALL with the t(1;19).[66]

      The t(1;19) had been associated with inferior outcome in the context of antimetabolite-based therapy,[67] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[64,68] However, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) on which all patients were treated without cranial radiation, patients with the t(1;19) had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[69,70]

      The t(17;19) resulting in the TCF3-HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3-HLF fusion is associated at diagnosis with disseminated intravascular coagulation and with hypercalcemia. Outcome is very poor for children with the t(17;19), with a literature review noting mortality for 20 of 21 cases reported.[71] In addition to the TCF3-HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).[65]

    • DUX4-rearranged ALL with frequent ERG deletions

      Approximately 5% of standard-risk and 10% of high-risk pediatric precursor B-cell ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[72,73] The frequency in older adolescents (aged >15 years) is approximately 10%. The most common rearrangement produces IGH-DUX4 fusions, with ERG-DUX4 fusions also observed. Approximately 50% of DUX4-rearranged cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes,[72,73] and DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with these focal deletions in ERG.[5,6,7]IKZF1 alterations are observed in 35% to 40% of DUX4-rearranged ALL.[72,73]ERG deletion connotes an excellent prognosis, with OS exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[5,6,7] Patients with DUX4 rearrangements who lack ERG deletion also appear to have favorable prognosis.[73]

    • MEF2D-rearranged ALL

      Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 4% of childhood ALL cases.[74,75] Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[74,76] The interstitial deletion producing the MEF2D-BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D-CSFR1 that have a Philadelphia chromosome (Ph)–like gene expression profile.[74,77] The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[74,75] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS was 72% (standard error, ±10%), which was inferior to that for other patients.[74]

    • ZNF384-rearranged ALL

      ZNF384 is a transcription factor that is rearranged in approximately 4% to 5% of pediatric B-cell ALL cases.[74,78,79] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[74,78,79]ZNF384 rearrangement does not appear to confer independent prognostic significance.[74,78,