| RRC ID |
86154
|
| Author |
Zang W, Koike Y, Nishimura K, Tanaka A, Yamazaki H, Yamasaki T, Ito H, Zhang Y, Aoyama Y, Saika W, Xiao M, Hasegawa C, Kunimoto H, Nakajima H, Ishikawa F, Takaori-Kondo A, Inoue D.
|
| Title |
BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia.
|
| Journal |
Sci Rep
|
| Abstract |
EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic BCL-2 inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.
|
| Volume |
15(1)
|
| Pages |
37099
|
| Published |
2025-10-23
|
| DOI |
10.1038/s41598-025-21034-1
|
| PII |
10.1038/s41598-025-21034-1
|
| PMID |
41131284
|
| PMC |
PMC12549952
|
| MeSH |
Animals
Antineoplastic Agents / pharmacology
Bridged Bicyclo Compounds, Heterocyclic* / pharmacology
Bromodomain Containing Proteins
Cell Cycle Proteins* / antagonists & inhibitors
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm* / drug effects
Drug Resistance, Neoplasm* / genetics
Gene Rearrangement*
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Leukemia, Myeloid, Acute* / pathology
MDS1 and EVI1 Complex Locus Protein* / genetics
Mice
Proto-Oncogene Proteins c-myb
Sulfonamides* / pharmacology
Transcription Factors* / antagonists & inhibitors
Transcription Factors* / genetics
Transcription Factors* / metabolism
|
| IF |
3.998
|
| Resource |
| Mice |
RBRC09508 |
