RUNX1 Mutations in Pediatric AML: A Report From the Children's Oncology Group.

Abstract 2614

Poster Board II-590

The RUNX1 gene (previously AML1) encodes the alpha subunit of core binding factor (CBFα), which is implicated in normal and malignant hematopoiesis. Translocations involving RUNX1 have been associated with favorable prognosis in acute leukemias (e.g., t(8;21) in AML and t(12;21) in ALL). Point mutations of RUNX1 have been identified in exon 3 and exon 8 of the RUNX1 gene in a subset of AML patients and are most closely associated with MDS associated AML and AML subtype M0. We evaluated the prevalence and prognostic significance of RUNX1 mutations in pediatric patients with de novo AML treated on pediatric AML trials CCG-2941 and CCG-2961. Initial evaluation of exon 3 and exon 8 of the RUNX1 gene was conducted on a cohort of 100 randomly selected patient specimens. In this initial analysis, we identified 4 missense mutations of exon 3 that caused a change in codon 56. No exon 8 mutations were identified. Subsequent molecular genotyping of the remaining 484 patient specimens were limited to exon 3. Of the 584 diagnostic specimens tested, a missense mutation of exon 3 was detected in 19 patients (3.3%). All detected mutations occurred at nucleotide 167 (T to C) causing a leucine to serine substitution at codon 56 (L56S). Additionally, two patients had a synonymous mutation (G to A at nucleotide 183, P61P) and were considered wild type. Demographics, laboratory characteristics and clinical outcome were compared between those with and without RUNX1 mutations. There was no significant difference with regard to age, gender or race between these groups. Those with RUNX1 mutations had a significantly lower prevalence of organomegaly (16% vs. 42%, p=0.02) and significantly higher rate of extramedullary disease (chloroma 26% vs. 10%, p=0.04). There was no significant difference in association with other known cytogenetic abnormalities or risk groupings (standard, low, or high risk grouping on these studies). t(8;21) translocations were detected in 22% of those with RUNX1 mutations compared to 16% in those without mutation (p=0.6), and there was no RUNX1 mutation detected in patients with inv(16). Of the 85 patients with FLT3/ITD, NPM1 or CEBPA mutations, only 3 patients had a concomitant RUNX1 mutation (2 with FLT3/ITD and 1 with NPM1 mutation). Remission induction rate was compared between patients with and without RUNX1 mutations. Those with RUNX1 mutations had a similar CR rate to those without mutations (89% vs. 79%, p=0.4). Overall survival from remission for patients with and without RUNX1 mutation was 39 ± 25% and 60 ± 5% respectively (p=0.1) with a corresponding disease-free survival of 34 ± 24% vs. 49 ± 5% (p=0.25). RUNX1 mutations may represent a biologically distinct group that presents in 3.3% of pediatric AML patients across different morphologic and cytogenetic populations. Alterations of RUNX1 affect signal transduction pathways and may be exploited in defining a population for directed and risk based therapy.