Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
X
X
publication

Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia


Donia M. Moujalled et al.
Blood
Abstract

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.



Authors

Donia M. Moujalled



VIEW

publication
Impact of Clonal Architecture on Clinical Course and Prognosis in Patients With Myeloproliferative Neoplasms
Luque Paz, Damien
HemaSphere
publication
Massively parallel base editing to map variant effects in human hematopoiesis
Jorge D. Martin-Rufino
Cell
publication
Spectrum of clonal hematopoiesis in VEXAS syndrome
Fernanda Gutierrez-Rodrigues
Blood
publication
Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
Inge van der Werf
Cell Reports Medicine
REQUEST QUOTE