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Pediatric acute lymphoblastic leukemia
Figure 1. Change in overall survival of pediatric patients treated on the historical St. Jude Total Therapy studies.
arrays. In addition, the transcriptomic profiles and co- occurring genetic alterations (e.g., Ras pathway and CREBBP alterations) of near-haploid and high-hyper- diploid ALL are similar, suggesting a common origin for these entities.15 ALL with intrachromosomal amplifica- tion of chromosome 21 (iAMP21) is most common in older children and is associated with poor prognosis, which has been improved with intensive treatment.39
Of the subtypes characterized by translocations, the most common in childhood B-ALL is t(12;21)(p13;q22) encoding ETV6-RUNX1, which is typically cryptic on cytogenetic analysis and is associated with favorable prognosis. The t(1;19)(q23;p13) translocation and variants encode TCF3-PBX1,40 which is more common in African Americans and is associated with more frequent central nervous system (CNS) relapse and inferior outcomes with older,41 but not contemporary, treatment regimens.9 The t(9;22)(q34;q11.2) translocation results in the formation of the Philadelphia chromosome that encodes BCR-ABL1 and is found in a subset of childhood ALL that was also associated with unfavorable outcomes, although the prognosis has now been improved with combined chemotherapy and tyrosine kinase inhibition.42 Rearrangement of KMT2A (MLL) at 11q23 to >80 part- ners, most commonly t(4;11)(q21;q23) encoding KMT2A- AFF1, is common in infant ALL and is associated with a dismal prognosis.
Genomic analyses, particularly transcriptome sequenc- ing, have identified multiple new subtypes not evident on cytogenetic analysis because of cryptic and/or diverse rearrangements or sequence mutations acting as driver lesions. ETV6-RUNX1–like ALL is characterized by a
gene expression profile and immunophenotype (CD27+, CD44 low/negative) similar to that of ETV6-RUNX1 ALL.43,44 Such patients harbor alternate gene fusions or copy number alterations in ETS-family transcription fac- tors (ETV6, ERG, FLI1), IKZF1, or TCF3. ETV6-RUNX1– like ALL occurs almost exclusively in children (represent- ing ~3% of pediatric ALL) and is associated with relative- ly favorable prognosis.15
Translocation of DUX4, encoding a double-homeobox transcription factor, to the immunoglobulin heavy-chain locus (IGH) is also cytogenetically cryptic and is found in 5-10% of B-ALL. The translocation results in overexpres- sion of DUX4 protein lacking the C-terminal domain. This truncated protein binds an intragenic region of the ETS-family transcription factor ERG (ETS-related gene), resulting in profound transcriptional deregulation of ERG. This in turn commonly results in expression of a C-termi- nal ERG protein fragment and/or ERG deletion. DUX4- rearranged B-ALL has a distinctive gene expression profile and immunophenotype (CD2±, CD371+), and despite the deletion of IKZF1 (otherwise an adverse prognostic factor in ALL) in approximately 40% of cases, the outcome is typically excellent.20,45
ZNF384 rearrangement defines a distinct group of acute leukemias that may manifest as B-ALL (often with aber- rant myeloid marker expression) or B/myeloid mixed- phenotype acute leukemia (MPAL; MPO-positive leukemia). ZNF384 rearrangement is observed in 6% of childhood B-ALL and in 48% of childhood (but notably not adult) B/myeloid MPAL.15,46-48 ZNF384-like cases, often with ZNF362 rearrangements, are also observed. Both ZNF384 and ZNF362 encode C2H2-type zinc-finger tran-
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