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 ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NIH 5K08CA230172 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Memorial Sloan Kettering Cancer Center gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors