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.
Myeloproliferative neoplasms (MPN) are characterized by uncontrolled expansion of myeloid cells, disease‐related mutations in certain driver‐genes including JAK2, CALR, and MPL, and a substantial ...risk to progress to secondary acute myeloid leukemia (sAML). Although behaving as stem cell neoplasms, little is known about disease‐initiating stem cells in MPN. We established the phenotype of putative CD34+/CD38− stem cells and CD34+/CD38+ progenitor cells in MPN. A total of 111 patients with MPN suffering from polycythemia vera, essential thrombocythemia, or primary myelofibrosis (PMF) were examined. In almost all patients tested, CD34+/CD38− stem cells expressed CD33, CD44, CD47, CD52, CD97, CD99, CD105, CD117, CD123, CD133, CD184, CD243, and CD274 (PD‐L1). In patients with PMF, MPN stem cells often expressed CD25 and sometimes also CD26 in an aberrant manner. MPN stem cells did not exhibit substantial amounts of CD90, CD273 (PD‐L2), CD279 (PD‐1), CD366 (TIM‐3), CD371 (CLL‐1), or IL‐1RAP. The phenotype of CD34+/CD38− stem cells did not change profoundly during progression to sAML. The disease‐initiating capacity of putative MPN stem cells was confirmed in NSGS mice. Whereas CD34+/CD38− MPN cells engrafted in NSGS mice, no substantial engraftment was produced by CD34+/CD38+ or CD34− cells. The JAK2‐targeting drug fedratinib and the BRD4 degrader dBET6 induced apoptosis and suppressed proliferation in MPN stem cells. Together, MPN stem cells display a unique phenotype, including cytokine receptors, immune checkpoint molecules, and other clinically relevant target antigens. Phenotypic characterization of neoplastic stem cells in MPN and sAML should facilitate their enrichment and the development of stem cell‐eradicating (curative) therapies.
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