Abstract B16: MECOM dysregulation is associated with poor outcome in pediatric therapy-related myeloid neoplasms

Abstract

Abstract Therapy-related myeloid neoplasms (tMN) occur in children as a consequence of cytotoxic therapies used to treat childhood malignancies, are typically resistant to conventional chemotherapies, require hematopoietic cell transplantation as the only curative option, and typically have a dismal prognosis. While the genomic alterations that drive tMN in children have yet to be comprehensively described, alterations involving the MECOM locus have been described in some myeloid neoplasms like tMN. Overexpression of MECOM is associated with poor prognosis in myeloid malignancies, is present in ~10% of adult cases, and occurs at an increased frequency in pediatric AML with KMT2A rearrangements (KMT2Ar). RNA sequencing from a cohort of 56 pediatric tMN cases collected at St. Jude shows that 24 (43%) cases within our cohort express high levels of MECOM (FPKM value >5). In these 24 cases, we identified one with a canonical fusion (RUNX1-MECOM), one with a NUP98 fusion (NUP98-HHEX), and 18 with KMT2Ar. Whole-genome sequencing demonstrated that two of the remaining MECOMHigh cases have a t(2;3)(p21;q26.2) involving MECOM on chromosome 3 and noncoding regions of chromosome 2 adjacent to ZFP36L2, a gene highly expressed in hematopoietic cells. Further, ENCODE data support that this region of the genome is an active enhancer, suggesting a proximity effect in which this enhancer has been hijacked to drive high levels of MECOM expression. The two remaining cases with aberrant and unexplained MECOM expression are currently under evaluation. In our cohort, MECOM expression levels are predictive of a worse outcome (overall survival at 2 years: MECOMHigh=12.5% vs. MECOMLow=40.6%; log rank p<0.01). Although KMT2Ar was frequently present in our cohort 28/56 (50%) and enriched in the MECOMHigh group (MECOMHigh=75% (18/24) vs. MECOMLow=31% (10/32; p<0.01), high MECOM expression did not confer a significant survival difference within the KMT2Ar group (overall survival at 2 years: MECOMHigh=16.7% vs. MECOMLow=40%; log rank p=0.33). In conclusion, we report a large cohort of pediatric tMN and show that high levels of MECOM expression predicts a worse outcome. Additionally, we identify enhancer hijacking as the mechanism through which at least a portion of high MECOM expression may be explained. Citation Format: Tamara Lamprecht, Jason R. Schwartz, Jing Ma, Michael P. Walsh, Jeffery M. Klco. MECOM dysregulation is associated with poor outcome in pediatric therapy-related myeloid neoplasms [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B16.