We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11; q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.

To identify risk variants for childhood acute lymphoblastic leukemia (ALL) we conducted a genome-wide association study of 2 case-control series, analyzing the genotypes of 291,423 tagging SNP genotypes in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601; OR = 1.69, P = 1.20 x 10-19), 10q21.2 (ARIDB5, rs7089424; OR = 1.65, P = 6.69 x 10-19) and 14q11.2 (CEBPE, rs2239633; OR = 1.34, P = 2.88 x 10-7). The 10q21.2 (ARIDB5) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide novel insight into disease causation of this hematological cancer; notably all 3 risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.

Key Points• RAS pathway mutations are prevalent in relapsed childhood ALL, and KRAS mutations are associated with a poorer overall survival.• RAS pathway mutations confer sensitivity to mitogenactivated protein kinase kinase inhibitors.For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www. clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL. (Blood. 2014;124(23):3420-3430)