Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Eisenwort, G; Sadovnik, I; Keller, A; Ivanov, D; Peter, B; Berger, D; Stefanzl, G; Bauer, K; Slavnitsch, K; Greiner, G; Gleixner, KV; Sperr, WR; Willmann, M; Sill, H; Bettelheim, P; Geissler, K; Deininger, M; Rülicke, T; Valent, P.
Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia.
Leukemia. 2021; 35(11):3176-3187
Doi: 10.1038/s41375-021-01227-z
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- Co-authors Med Uni Graz
- Sill Heinz
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- Abstract:
- Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and 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.