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.
- 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: [email protected].
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.