6532 Background: PTPN11 mutations are associated with worse treatment outcomes in acute myeloid leukemia (AML) and frequently co-occur with NPM1 mutations. However, the impact of concurrent NPM1 mutations in PTPN11 mut myeloid leukemia is not well understood. This work aims to 1) characterize genomic features of a single-center cohort of patients with PTPN11 mut /NPM1 wt and PTPN11 mut / NPM1 mut -myeloid leukemia and 2) assess associated transcriptomic patterns. Methods: Patients with myeloid leukemia with PTPN11 and/or NPM1 mutations observed in blood (PB) or bone marrow (BM) were identified from the UMass Leukemia Registry. Next-generation sequencing (NGS) data were annotated for co-occurring variants and cytogenetic abnormalities. RNA-seq data from PB and BM samples from the Beat AML 1.0 trial were accessed via The Cancer Genome Atlas. Sample IDs with PTPN11 mut , NPM1 mut and PTPN11 mut /NPM1 mut were identified using the Vizome platform. High-throughput analysis of these samples and NPM1/PTPN11 wt was then performed using DESeq2. Results: 107 patients with myeloid leukemias at UMass Cancer Center harboring PTPN11 mutations (n = 34) or NPM1 mutations (n=74) were identified, 14 of whom had both. Subgroup analysis of chromosomal maps of PTPN11 mut /NPM1 mut cohort and PTPN11 mut / NPM1 wt cohort showed that the PTPN11 mut / NPM1 wt group had a higher cytogenetic abnormality burden compared to the PTPN11 mut /NPM1 mut group, demonstrating 18 observations of 12 distinct abnormalities compared to 5 observations of 3 distinct abnormalities, respectively. Analysis of RNA-seq from BM tissue of PTPN11 mut /NPM1 wt AML (n = 6) from the Beat AML 1.0 dataset revealed only 22 differentially expressed genes compared to PTPN11 wt /NPM1 wt samples. Of these, 12 were mitigated in the PTPN11 mut /NPM1 mut (n = 9) group. This trend was less pronounced in analysis of PB tissue. However, review of 20 most differentially expressed genes of both BM and PB in the PTPN11 mut /NPM1 wt group revealed many changes in long intergenic non-coding RNAs (lincRNAs). Conclusions: Genomic analysis of PTPN11 mut /NPM1 wt BM and PB highlighted widespread cytogenetic heterogeneity compared to the PTPN11 mut NPM1 mut subgroup. RNAseq analysis of PTPN11 mut BM and PB revealed significant differential expression in multiple lincRNAs, particularly in BM. These changes were mitigated in the double mutant group. Larger studies are needed to validate these findings and investigate whether presence of subtle regulatory shifts serve as a driving factor in the poor outcomes underlying PTPN11 mut AML. Further chromatin accessibility profiling studies may help elucidate the regulatory mechanisms driving these transcriptomic changes.
Maheswaran et al. (Wed,) studied this question.