1. Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia
- Author
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Daniela Berger, Alexandra Keller, Georg Greiner, Daniel Ivanov, Thomas Rülicke, Peter Bettelheim, Michael W. Deininger, Irina Sadovnik, Heinz Sill, Karin Bauer, Michael Willmann, Karoline V. Gleixner, Wolfgang R. Sperr, Gregor Eisenwort, Barbara Peter, Peter Valent, Gabriele Stefanzl, Katharina Slavnitsch, and Klaus Geissler
- Subjects
Male ,0301 basic medicine ,Cancer Research ,CD52 ,CD33 ,Chronic myelomonocytic leukemia ,Antigens, CD34 ,Apoptosis ,Mice, SCID ,Biology ,CD38 ,Article ,Venetoclax ,Mice ,03 medical and health sciences ,0302 clinical medicine ,AML ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Secondary Acute Myeloid Leukemia ,Aged ,Cell Proliferation ,Aged, 80 and over ,Leukemia, Myelomonocytic, Chronic ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Leukemic Stem Cells ,Leukemia, Myeloid, Acute ,Leukemia ,Phenotype ,030104 developmental biology ,Oncology ,Case-Control Studies ,030220 oncology & carcinogenesis ,NSGS Mice ,Neoplastic Stem Cells ,Cancer research ,Female ,sense organs ,Interleukin-3 receptor ,Stem cell - Abstract
Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes and a substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38– fraction of the malignant clone. Whereas CD34+/CD38– cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34– monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38– cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.
- Published
- 2021