Abstract
Abstract 3546
Rearrangements of the mixed lineage leukemia (MLL) gene are associated with the development of acute leukemia, and a variety of translocation partners have been described to date. In acute myeloid leukemia (AML), the translocation t(9;11)(p22;q23), resulting in the MLLT3-MLL fusion gene, is the most common genetic event involving MLL. The translocation t(9;11) can occur de novo, or as a consequence of previous chemotherapy (t-AML). Both types exhibit significant biological and clinical heterogeneity, and cooperating genetic events have been implicated underlying these heterogeneous phenotypes. To identify additional genomic abnormalities in AML with t(9;11), we performed high-resolution, genome-wide analysis of DNA copy number alterations (CNA) and copy neutral loss of heterozygosity (CN-LOH) using Affymetrix 6.0 single nucleotide polymorphism (SNP) microarrays in 34 AMLs with t(9;11) [de novo AML, n=22; t-AML, n=12]. Samples were also analyzed for AML-associated mutations: FLT3 [internal tandem duplication (ITD; 2/33); tyrosine kinase domain (TKD; 2/26)], NPM1 (0/28), CEBPA (0/23), IDH1 (0/28), IDH 2 (0/28), DNMT3A (0/19), NRAS (0/6); and deregulated expression of EVI1 (8/16). Control DNA from remission bone marrow or peripheral blood was available for paired analysis in 12 (33%) cases. Data were processed using reference alignment, dChipSNP, and circular binary segmentation. Paired analysis revealed a mean of 1.9 somatic CNAs per case (range: 0–12); 45% of cases lacked any CNAs. Deletions were more common than gains (1.73 losses/case vs. 0.25 gains/case; p =0.04). There were no significant differences in the mean number of CNAs between de novo and therapy-related cases (de novo AML: 1.0, range: 0–2; t-AML: 2.7, range: 0–12; p =0.93). Recurrent deletions were detected at chromosomal bands 7q36.1–36.2 (n=2) and at the chromosomal translocation breakpoint at 11q23 (n=2). The del(7q36.1–36.2) overlapped with a minimally deleted region at 7q36.1 that we previously identified in 8% of core-binding factor AML containing only 4 genes (PRKAG2, GALNT11, GALNTL5 and MLL3). The only gene contained in both regions was MLL3, a member of the mixed-lineage leukemia gene family. The most recurrent CNA was trisomy 8 (n=5), also detected by conventional cytogenetics in all 5 cases. Novel recurrent focal gains were identified at 9p22.1 (n=2; size: 341 Kb) and at 13q21.33-q22.1 (n=2; size: 1021 Kb) with each region containing genes potentially involved in cancer pathogenesis (ACER2 in 9p; KLF5 in 13q). Analysis of CN-LOH revealed no such lesion in any of the cases. In summary, our data provide a comprehensive survey of CNAs in a well characterized cohort of AMLs with t(9;11). These data demonstrate a very low occurrence of CNAs, with no significant differences between de novo and therapy-related cases and complete absence of CN-LOH. Interestingly, a number of novel recurrent secondary genetic alterations were identified. Determining the functional role of these lesions in leukemogenesis and drug resistance should provide new insights into t(9;11)-bearing AMLs.
Disclosures:
No relevant conflicts of interest to declare.
Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia
