Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling

  • Leukemia. 2022 Dec 22. doi: 10.1038/s41375-022-01798-5.
Nicholas R Anderson  1 ,  Vipul Sheth  1 ,  Hui Li  1 ,  Mason W Harris  1 ,  Shaowei Qiu  1  2 ,  David K Crossman  3 ,  Harish Kumar  1 ,  Puneet Agarwal  4 ,  Takashi Nagasawa  5 ,  Andrew J Paterson  6 ,  Robert S Welner  1 ,  Ravi Bhatia  7
Affiliations
  • 1. Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.
  • 3. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 4. Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 5. Laboratory of Stem Cell Biology & Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
  • 6. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 7. Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. [email protected].
PMID: 36550214 DOI: 10.1038/s41375-022-01798-5
Abstract

Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.

Products