3031 – Chromothripsis and leukemic transformation in MPN

The accelerated-phase myeloproliferative neoplasms (APMPN) are an area of unmet clinical need, where an aggressive and usually fatal leukemia arises from a precursor clonal chronic bone marrow condition. How and why up to 20% of MPN patients (pts) transform is poorly understood. We performed SNP karyotyping and a myeloid sequencing panel to enable integrated copy number and mutation profiling in 64 APMPN pts. We observed a recurrent pattern of chromothripsis involving chromosome 21 with focal and multiple amplifications of chr21q22 (‘chr21amp’), occurring in ∼25% of an otherwise genomically heterogeneous cohort. Chr21amp patients had a particularly aggressive and treatment-resistant phenotype, with significantly impaired overall survival. Using a multi-omics approach leveraging whole genome sequencing, single cell and bulk RNA-seq and ATAC-seq, we profiled the structural variant and defined the 2.7Mb minimally amplified region shared across cases. The chr21amp event was highly clonal and led to marked upregulation in expression and accessibility of DYRK1A, a serine threonine kinase and transcription factor. We show that DYRK1A is a central node at the nexus of multiple cellular functions critical for APMPN cell survival, including DNA repair and STAT signaling pathways. In functional studies, DYRK1A was essential for APMPN cell line survival and proliferation. Transplantation of DYRK1A-KO APMPN HEL or SET2 cell clones into mice led to a reduced ability to propagate leukemia in the host animal and a survival advantage vs wild type. Exposing primary pt CD34+ cells to DYRK1A inhibitors induced cell death at low doses, while healthy control CD34+ cells were unaffected. To our knowledge, this is the first report defining a chromothripsis event as a prognostic biomarker linked to a tractable therapeutic target, a concept that may be more broadly applicable in cancer.