The value of molecular stratification for CEBPA DM and NPM1 MUT FLT3 WT genotypes in older patients with acute myeloid leukaemia

Older adult patients (≥60 years) with acute myeloid leukaemia (AML) are generally considered to be poor‐risk and there is limited information available regarding risk stratification based on molecular characterization in this age group, particularly for the double‐mutant CEBPA (CEBPA DM) genotype. To investigate whether a molecular favourable‐risk genotype can be identified, we investigated CEBPA, NPM1 and FLT3 status and prognostic impact in a cohort of 301 patients aged 60 years or more with intermediate‐risk cytogenetics, all treated intensively. Overall survival (OS) at 1 year was highest in the 12 patients (4%) that were CEBPA DM compared to the 76 (28%) with a mutant NPM1 and wild‐type FLT3 (NPM1 MUT FLT3 WT) genotype or all other patients (75%, 54%, 33% respectively), with median survival 15·2, 13·6 and 6·6 months, although the benefit was short‐term (OS at 3 years 17%, 29%, 12% respectively). Combination of the CEBPA DM and NPM1 MUT FLT3 WT genotype patients defined a molecular group with favourable prognosis (P < 0·0001 in multivariate analysis), with 57% of patients alive at 1 year compared to 33% for all other patients. Knowledge of genotype in older cytogenetically intermediate‐risk patients might influence therapy decisions

Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia

Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites. Analysis of 5′-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provides important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy–induced T-ALL, suggesting that such events occur at preferential sites in the noncoding genome.National Institute for Health Research (Great Britain). Biomedical Research CentreHope Funds for Cancer Research Grillo-Marxuach Family Fello