| Autor: |
Miriam Erlacher, Ying Wu, Patricia Zehnle, Naile Koleci, Geoffroy Andrieux, Lorena Gallego Villar, Jovana Rajak, Konrad Aumann, Melanie Boerries, Charlotte Niemeyer, Sheila Bohler, Christian Flotho |
| Rok vydání: |
2023 |
| Popis: |
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 both leukemic burden and risk of relapse. 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 but also promotes the differentiation of JMML cells towards mature myeloid cells. 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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