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

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          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.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          2159-8290
          2159-8274
          Dec 01 2021
          : 11
          : 12
          Affiliations
          [1 ] Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
          [2 ] Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
          [3 ] Center of Regenerative Medicine, Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
          [4 ] Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
          [5 ] Incyte Research Institute, Wilmington, Delaware.
          Article
          NIHMS1722520 2159-8290.CD-20-1652
          10.1158/2159-8290.CD-20-1652
          8716669
          34193440
          c39f75d6-897a-4253-9e08-213039fa50cb
          History

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