2. Academic Validation
  3. BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia

  • Leukemia. 2023 Nov 9. doi: 10.1038/s41375-023-02079-5.
Ying Wu 1 2 3,  Patricia M A Zehnle 1 4,  Jovana Rajak 1 5,  Naile Koleci 1,  Geoffroy Andrieux 6,  Lorena Gallego-Villar 1,  Konrad Aumann 7,  Melanie Boerries 5 8,  Charlotte M Niemeyer 1,  Christian Flotho 1 8,  Sheila Bohler 1,  Miriam Erlacher 9
Affiliations

Affiliations

  • 1 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 2 Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.
  • 4 Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 5 Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
  • 6 Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 7 University Medical Center Freiburg, Institute of Surgical Pathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 8 German Cancer Consortium (DKTK), Partner Site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Miriam.erlacher@uniklinik-freiburg.de.
PMID: 37945692 DOI: 10.1038/s41375-023-02079-5
Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active Ras signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since Ras signaling is known to interfere with the intrinsic Apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both Mcl-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic Mcl-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to Bcl-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable Mcl-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.

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