A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Abstract

ABSTRACTMyeloproliferative neoplasms (MPNs) are chronic blood diseases with significant morbidity and mortality. While sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically-engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDXs). These PDXs robustly engrafted patient cells which recapitulated the patient’s genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify MF patients at-risk for sAML transformation, and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology.STATEMENT OF SIGNIFICANCEAlthough the genetic events driving myeloproliferative neoplasms (MPNs) are well-defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a patient-derived xenograft (PDX) system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacological manipulation.