2. Academic Validation
  3. Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia

Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia

  • Stem Cell Reports. 2023 Dec 6:S2213-6711(23)00452-6. doi: 10.1016/j.stemcr.2023.11.003.
Yanchun Li 1,  Christopher S Seet 2,  Ryan Mack 3,  Kanak Joshi 3,  Austin P Runde 3,  Patrick A Hagen 2,  Kevin Barton 2,  Peter Breslin 4,  Ameet Kini 5,  Hong-Long Ji 6,  Jiwang Zhang 7
Affiliations

Affiliations

  • 1 Blood Disease Laboratory, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710126, P.R. China.
  • 2 Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Medical Center, Maywood, IL 60153, USA; Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA.
  • 3 Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Medical Center, Maywood, IL 60153, USA; Departments of Cancer Biology and Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL 60153, USA.
  • 4 Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Medical Center, Maywood, IL 60153, USA; Departments of Biology, Molecular/Cellular Physiology, and Cancer Biology, Loyola University Medical Center, Maywood, IL 60153, USA.
  • 5 Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
  • 6 Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA.
  • 7 Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Medical Center, Maywood, IL 60153, USA; Departments of Cancer Biology and Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL 60153, USA; Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA. Electronic address: jzhang@luc.edu.
PMID: 38101400 DOI: 10.1016/j.stemcr.2023.11.003
Abstract

Lymphoid-primed multipotent progenitor (LMPP)-like and granulocyte-monocyte progenitor (GMP)-like leukemia stem cells (LSCs) co-exist in the blood of most patients with acute myeloid leukemia (AML). Complete elimination of both types of LSCs is required to cure AML. Using an MLL-AF9-induced murine AML model, we studied the role of hematopoietic cytokines in the survival of LMPP- and GMP-like LSCs. We found that SCF or FLT3L promotes the survival of LMPP-like LSCs by stimulating Stat5-mediated Mcl1 expression, whereas interleukin-3 (IL-3) or IL-6 induces the survival of GMP-like LSCs by stimulating STAT3/nuclear factor κB (NF-κB)-mediated Bcl2 expression. Functional study demonstrated that, compared to AML cells cultured in IL-3 and IL-6 medium, AML cells in SCF- or Flt3L-only culture are highly clonogenic in in vitro culture and are highly leukemogenic in vivo. Our study suggests that co-inhibition of both STAT5-MCL1 and STAT3/NF-κB-BCL2 signaling might represent an improved treatment strategy against AML, specifically AML cases with a monocytic phenotype and/or FLT3 mutations.

Keywords

AML; Bcl2; Mcl1; hematopoietic cytokines; leukemia stem cells; survival signaling.

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