Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia

Biomarker Research

Jiejing Qian¹  Yi Zhang¹  Yungui Wang¹  Yinjun Lou¹  Jie Jin²  Honghu Zhu³  Xiang Zhang³  Huafeng Wang³  Pengxu Qian⁴ 

[1] Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Rd, 310003, Hangzhou, Zhejiang, China;Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China;Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Rd, 310003, Hangzhou, Zhejiang, China;Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China;Zhejiang University Cancer Center, Zhejiang, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China;Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Rd, 310003, Hangzhou, Zhejiang, China;Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, Zhejiang, China;Zhejiang University Cancer Center, Zhejiang, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China;Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121, Hangzhou, China;Zhejiang University Cancer Center, Zhejiang, Hangzhou, China;Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China;Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121, Hangzhou, China;

关键词: Venetoclax;    Acquired resistance;    Acute myeloid leukemia;   

DOI  :  10.1186/s40364-021-00288-7

来源: Springer

【 摘 要 】

Venetoclax (VEN) plus azacitidine has become the first-line therapy for elderly patients with acute myeloid leukemia (AML), and has a complete remission (CR) plus CR with incomplete recovery of hemogram rate of ≥70%. However, the 3-year survival rate of these patients is < 40% due to relapse caused by acquired VEN resistance, and this remains the greatest obstacle for the maintenance of long-term remission in VEN-sensitive patients. The underlying mechanism of acquired VEN resistance in AML remains largely unknown. Therefore, in the current study, nine AML patients with acquired VEN resistance were retrospectively analyzed. Our results showed that the known VEN resistance-associated BCL2 mutation was not present in our cohort, indicating that, in contrast to chronic lymphocytic leukemia, this BCL2 mutation is dispensable for acquired VEN resistance in AML. Instead, we found that reconstructed existing mutations, especially dominant mutation conversion (e.g., expanded FLT3-ITD), rather than newly emerged mutations (e.g., TP53 mutation), mainly contributed to VEN resistance in AML. According to our results, the combination of precise mutational monitoring and advanced interventions with targeted therapy or chemotherapy are potential strategies to prevent and even overcome acquired VEN resistance in AML.

【 授权许可】

CC BY