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


Authors: Yoshimi, A.; Balasis, M. E.; Vedder, A.; Feldman, K.; Ma, Y.; Zhang, H.; Lee, S. C. W.; Letson, C.; Niyongere, S.; Lu, S. X.; Ball, M.; Taylor, J.; Zhang, Q.; Zhao, Y.; Youssef, S.; Chung, Y. R.; Zhang, X. J.; Durham, B. H.; Yang, W.; List, A. F.; Loh, M. L.; Klimek, V.; Berger, M. F.; Stieglitz, E.; Padron, E.; Abdel-Wahab, O.
Article Title: Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML
Abstract: 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. © 2017 by The American Society of Hematology.
Keywords: clinical article; controlled study; chronic myelomonocytic leukemia; gene mutation; human cell; genetics; janus kinase 2; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; stem cell factor; cell structure; spleen; granulocyte macrophage colony stimulating factor; neoplasm proteins; animal experiment; animal model; in vivo study; drug screening; pathology; mice, scid; xenograft model antitumor assays; pyrimidines; chimera; liver; xenograft; tumor protein; lung; immunophenotyping; neoplasm transplantation; flt3 ligand; pyrimidine derivative; mice, inbred nod; nonobese diabetic mouse; leukemia, myelogenous, chronic, bcr-abl positive; cd34 selection; graft recipient; scid mouse; peripheral blood mononuclear cell; myelodysplastic syndromes; clonogenesis; tumor engraftment; cancer transplantation; jak2 protein, human; cd135 antigen; juvenile myelomonocytic leukemia; cell self-renewal; interleukin 3; fms-like tyrosine kinase 3; xenotransplantation; bridged compound; pacritinib; humans; human; male; female; priority journal; article; heterografts; nod scid gamma mouse; antagonists and inhibitors; bridged-ring compounds; 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; flt3 protein, human; bone marrow derived mononuclear cell; leukemia, myelomonocytic, juvenile
Journal Title: Blood
Volume: 130
Issue: 4
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2017-07-27
Start Page: 397
End Page: 407
Language: English
DOI: 10.1182/blood-2017-01-763219
PUBMED: 28576879
PROVIDER: scopus
PMCID: PMC5533204
DOI/URL:
Notes: Article -- Export Date: 5 September 2017 -- Source: Scopus
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MSK Authors
  1. Virginia Klimek
    106 Klimek
  2. Michael Forman Berger
    373 Berger
  3. Sydney X Lu
    48 Lu
  4. Young Rock Chung
    46 Chung
  5. Stanley Chun-Wei Lee
    27 Lee
  6. Benjamin Heath Durham
    58 Durham
  7. Akihide   Yoshimi
    22 Yoshimi
  8. Justin   Taylor
    16 Taylor
  9. Wendy   Yang
    4 Yang
  10. Xiao Jing Zhang
    5 Zhang