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

Hamza Celik, Ethan Krug, Christine R. Zhang, Wentao Han, Nancy Issa, Won Kyun Koh, Hassan Bjeije, Ostap Kukhar, Maggie Allen, Tiandao Li, Daniel A.C. Fisher, Jared S. Fowles, Terrence N. Wong, Matthew C. Stubbs, Holly K. Koblish, Stephen T. Oh, Grant A. Challen

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Myeloproliferative neoplasms (MPN) are chronic blood diseases with significant morbidity and mortality. Although 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 (PDX). These PDXs robustly engrafted patient cells that 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 patients with MF 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. SIGNIFICANCE: Although the genetic events driving MPNs are well defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a PDX system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacologic manipulation.

Original languageEnglish
Pages (from-to)3126-3141
Number of pages16
JournalCancer discovery
Volume11
Issue number12
DOIs
StatePublished - Dec 2021

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