Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL, incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations), and a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

AUTHOR CONTRIBUTIONSCGM designed and coordinated the study, designed assays, performed experiments, analyzed data and wrote the manuscript JRC-U generated retroviral vectors and performed Ba/F3 assays LAAP performed JAK sequencing and quantitative PCR assays MLL performed PAR1 deletion genomic PCR WL performed statistical analysis JZ analyzed sequencing data Jing Ma analyzed microarray data EC-S performed flow cytometry and analyzed data RCH and CLW developed FISH assays Julia Meyer performed experiments and analyzed data FMM, AJC and NAH performed FISH assays and analyzed cytogenetic data RTW provided luciferase vectors JC designed subcloning vectors GB and AP provided patient samples SCR performed cytogenetic analysis SPH coordinated studies and sample collection JRD provided patient samples WLC provided patient samples, performed experiments and analyzed data KRR provided samples, performed experiments and analyzed data NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 May 1. Published in final edited form as:Nat Genet. SUMMARYAneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many patients lack a recurring chromosomal alteration. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, non-coding exon of P2RY8 to the coding region of CRLF2 (which encodes cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor). The P2RY8-CRLF2 fusion was identified in 7% of B-progenitor ALL cases, and was identified in over 50% of ALL cases arising in patients with Down syndrome (53% of 75 cases). CRLF2 alteration was associated with the presence of activating JAK mutations, and expression of P2RY8-CRLF2 together with JAK2 mutants resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3-IL7R cells, indicating that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.Chromosomal alterations are a hallmark of acute lymphoblastic leukemia (ALL), the commonest malignancy of childhood, and include aneuploidy (hyperdiploidy and hypodiploidy) and recurring chromosomal translocations, such as t(12;21) [ETV6-RUNX1], t (1;19) [TCF3-PBX1], t(9;22) [BCR-ABL1] and rearrangement of MLL 1 . These alterations are important events in leukemogenesis and influence response to therapy. However, up to onequarter of childhood ALL cases lack a recurring chromosomal alteration, and the genetic basis of these cases is poorly understood.To identify submicroscopic genetic alterations contributing to the pathogenesis of ALL, we previously performed high resolution profiling of DNA copy number alterations and loss of heterozygosity (LOH) using single nucleotide polymorphism (SNP) microarrays, and identified multiple recurring genetic alterations targeting key cellular pathways including lymphoid development, cell cycle regulation and tumor suppression2 , 3. These alterations included a novel deletio...

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of (- or -) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (, ,) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (, ,, and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes (, ,) in 6.3% or other kinases (, ,) in 4.6%, and mutations involving the Ras pathway (, ,, ) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.

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AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.