Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Akihide Yoshimi, Maria E. Balasis, Alexis Vedder, Kira Feldman, Yan Ma, Hailing Zhang, Stanley Chun Wei Lee, Christopher Letson, Sandrine Niyongere, Sydney X. Lu, Markus Ball, Justin Taylor, Qing Zhang, Yulong Zhao, Salma Youssef, Young Rock Chung, Xiao Jing Zhang, Benjamin H. Durham, Wendy Yang, Alan F. ListMignon L. Loh, Virginia Klimek, Michael F. Berger, Elliot Stieglitz, Eric Padron, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rgnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD341 cells (n 5 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n 5 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n 5 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD341 cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD341 cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n 5 4 patients, n 5 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.

Original languageEnglish (US)
Pages (from-to)397-407
Number of pages11
Issue number4
StatePublished - Jul 27 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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