Haematologica (Nov 2023)
<i>ASXL1</i> mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms
- Vladimir Riabov,
- Qingyu Xu,
- Nanni Schmitt,
- Alexander Streuer,
- Guo Ge,
- Lyndsey Bolanos,
- Mark Wunderlich,
- Johann-Christoph Jann,
- Alina Wein,
- Eva Altrock,
- Marie Demmerle,
- Sanjay Mukherjee,
- Abdullah Mahmood Ali,
- Felicitas Rapp,
- Verena Nowak,
- Nadine Weimer,
- Julia Obländer,
- Iris Palme,
- Melda Göl,
- Ahmed Jawhar,
- Ali Darwich,
- Patrick Wuchter,
- Christel Weiss,
- Azra Raza,
- Jason M. Foulks,
- Daniel T. Starczynowski,
- Feng-Chun Yang,
- Georgia Metzgeroth,
- Laurenz Steiner,
- Mohamad Jawhar,
- Wolf-Karsten Hofmann,
- Daniel Nowak
Affiliations
- Vladimir Riabov
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Qingyu Xu
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Nanni Schmitt
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Alexander Streuer
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Guo Ge
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
- Lyndsey Bolanos
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Mark Wunderlich
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Johann-Christoph Jann
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Alina Wein
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Eva Altrock
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Marie Demmerle
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Sanjay Mukherjee
- Myelodysplastic Syndromes Center, Columbia University Irving Medical Center, Columbia University, New York
- Abdullah Mahmood Ali
- Myelodysplastic Syndromes Center, Columbia University Irving Medical Center, Columbia University, New York
- Felicitas Rapp
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Verena Nowak
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Nadine Weimer
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Julia Obländer
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Iris Palme
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Melda Göl
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Ahmed Jawhar
- Department of Orthopedic Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Ali Darwich
- Department of Orthopedic Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Patrick Wuchter
- Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg-Hessen, Medical Faculty Mannheim, Heidelberg University
- Christel Weiss
- Department of Medical Statistics, Biomathematics and Information Processing, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Azra Raza
- Myelodysplastic Syndromes Center, Columbia University Irving Medical Center, Columbia University, New York
- Jason M. Foulks
- Sumitomo Pharma Oncology, Inc., Lehi, UT
- Daniel T. Starczynowski
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA
- Feng-Chun Yang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
- Georgia Metzgeroth
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Laurenz Steiner
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Mohamad Jawhar
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Wolf-Karsten Hofmann
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- Daniel Nowak
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim
- DOI
- https://doi.org/10.3324/haematol.2023.282921
- Journal volume & issue
-
Vol. 109,
no. 5
Abstract
Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMA) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5-azacytidine (5-AZA) could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in N=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene expression of the pro-apoptotic factor NOXA in ASXL1-mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.
