MPN Transformation Is Characterized By Heterogeneous Shifts In Lineage Character Resulting In Both HSC-Like And More Differentiated Lineage Signatures.

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have a propensity to transform to an accelerated or blast phase (MPN-AP/BP). The resulting disease has clinically similar manifestations to Acute Myeloid Leukemia (AML) but worse clinical outcomes. Here we present the first comprehensive description of the transcriptomic characteristics of MPN-AP/BP. Our analysis incorporates data from 261 patients of the BeatAML cohort and 56 MPN-AP/BP patients, 11 of whom had paired samples from before and after transformation. We establish that transformed MPN is a transcriptionally distinct entity from de novo AML and chronic phase MPNs. Genomic pathways traditionally associated with MPN pathogenesis, such as IL2/STAT5 signaling, IL6/JAK/STAT3 signaling, and NUP98/HOXA9 fusions, were enriched in chronic-phase MPNs but are absent in transformed disease, suggesting JAK2 directed therapy may be less effective in this disease phase. We also discovered that gene expression signatures associated with doxorubicin resistance are highly enriched in transformed MPNs, which may explain the lack of efficacy of standard AML therapies. In addition, we identify that lineage composition at the time of transformation may define distinct subsets of MPN-AP/BP patients, which may assist in the future development of novel treatment strategies. Key Points- Accelerated- and blast-phase transformed MPNs are a transcriptionally entities which are distinct from de novo AML. - Transformed MPNs may be characterized by their lineage characteristics, which can drive clinical behavior and account for their inferior overall survival - Gene expression signatures associated with doxorubicin resistance were highly enriched in transformed MPNs, which may explain the lack of effectiveness of anthracycline-based therapies