Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML

Autor: Csaba Ortutay, Anna Halpin-McCormick, Denis V. Baev, Eva Szegezdi, Sukhraj Pal Singh Dhami, Michael O'Dwyer, John Quinn, Afshin Samali, Corrado Santocanale, Ruth Morrell, Eimear O’ Reilly
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Myeloid
CD34
lcsh:Medicine
Cell Cycle Proteins
Drug resistance
Piperazines
Nitrophenols
0302 clinical medicine
Bone Marrow
hemic and lymphatic diseases
Tumor Microenvironment
lcsh:Science
Sulfonamides
Multidisciplinary
Cytarabine
3. Good health
Leukemia
Myeloid
Acute
Leukemia
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine.drug
Stromal cell
Daunorubicin
bcl-X Protein
Protein Serine-Threonine Kinases
Article
03 medical and health sciences
Antigens
CD
Cell Line
Tumor
medicine
Humans
Pyrroles
Protein Kinase Inhibitors
neoplasms
Piperidones
business.industry
Biphenyl Compounds
lcsh:R
medicine.disease
Cyclin-Dependent Kinase 9
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
lcsh:Q
Bone marrow
Stromal Cells
business
Zdroj: Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
Scientific Reports
ISSN: 2045-2322
Popis: Acute myeloid leukaemia (AML) is an aggressive cancer with 50–75% of patients relapsing even after successful chemotherapy. The role of the bone marrow microenvironment (BMM) in protecting AML cells from chemotherapeutics and causing consequent relapse is increasingly recognised. However the role that the anti-apoptotic Bcl-2 proteins play as effectors of BMM-mediated drug resistance are less understood. Here we show that bone marrow mesenchymal stromal cells (BMSC) provide resistance to AML cells against BH3-mimetics, cytarabine and daunorubicin, but this is not mediated by Bcl-2 and/or Bcl-XL as previously thought. Instead, BMSCs induced Mcl-1 expression over Bcl-2 and/or Bcl-XL in AML cells and inhibition of Mcl-1 with a small-molecule inhibitor, A1210477, or repressing its expression with the CDC7/CDK9 dual-inhibitor, PHA-767491 restored sensitivity to BH3-mimetics. Furthermore, combined inhibition of Bcl-2/Bcl-XL and Mcl-1 could revert BMSC-mediated resistance against cytarabine + daunorubicin. Importantly, the CD34+/CD38− leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-XL and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.
Databáze: OpenAIRE
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