Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia.

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.

SUBMITTER: Eisenwort G 

PROVIDER: S-EPMC7611912 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature