Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosomepositive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n ؍ 3), JAK2 (n ؍ 16), and JAK3 (n ؍ 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P ؍ 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL. IKAROS ͉ kinase ͉ mutationA cute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and despite high overall cure rates (1), ALL remains the second leading cause of cancer death in children. To improve outcome, it is necessary to identify highrisk patients at the time of diagnosis and then tailor therapy toward the genetic lesions driving their leukemia.Recent genome-wide analyses have identified common genetic alterations in childhood ALL that contribute to leukemogenesis (2, 3). To identify genetic lesions predictive of poor outcome in childhood ALL, we recently performed genomewide analysis of DNA copy number alterations, transcriptional profiling, and gene resequencing in a cohort of 221 children with B progenitor ALL predicted to be at high risk for relapse based on age and presentation leukocyte count (4). These patients were treated on the Children's Oncology Group P9906 trial by using an augmented reinduction/reconsolidation strategy (''Berlin-Frankfurt-Münster'' regimen) (5, 6). This cohort excluded patients with known good (ETV6-RUNX1 or trisomies 4 and 10) or very poor (hypodiploid, BCR-ABL1) risk sentinel genetic lesions, and it represents Ϸ12% of noninfant B precursor ALL cases (Table S1). Alteration of the lymphoid transcription factor IKZF1 (IKAROS) was associated with poor outcome and a leukemic cell gene expression signature highly similar to that of BCR-ABL1...
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these highrisk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ؎ 5.1%, compared with 63.5% ؎ 3.7% for the cohort (P ؍ .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapsefree survival (21.0% ؎ 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy. (Blood. 2010; 116(23):4874-4884)
To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with highrisk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n ؍ 109) versus high (4-year RFS, 50%, n ؍ 98; P < .001). In multivariate analysis, the gene expression classifier (P ؍ .001) and flow cytometric measures of minimal residual disease (MRD; P ؍ .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low-(87% RFS), intermediate-(62% RFS), or high-(29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent highrisk ALL cohort (P ؍ .006) and retained independent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures
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