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

Leukemia. 2021 Nov;35(11):3176-3187. doi: 10.1038/s41375-021-01227-z. Epub 2021 Mar 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, CD34 / immunology*
  • Antigens, CD34 / metabolism
  • Apoptosis
  • Case-Control Studies
  • Cell Proliferation
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myelomonocytic, Chronic / complications*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Phenotype*
  • Prognosis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antigens, CD34