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Publications

Acquired mutations in BAX confer resistance to BH3-mimetic therapy in Acute Myeloid Leukemia


Moujalled DM, Brown FC, Chua CC, Dengler MA, Pomilio G, Anstee NS, Litalien V, Thompson ER, Morley TD, MacRaild S, Tiong IS, Morris R, Dun K, Zordan AC, Shah JS, Banquet S, Halilovic E, Morris EJ, Herold MJ, Lessene GL, Adams JM, Huang DCS, Roberts AW, Blombery P, Wei AH.
Blood Oct 2022
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 pre-leukemic 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 represents a novel mechanism of resistance to BH3-mimetics and a potential barrier to longer-term efficacy of drugs targeting BCL-2 in AML.

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Area

Heme

Institution Type

Academia

Indication / Modality

Acute Myleoid Leukemia (AML)

Goal of Study

Clinical Profiling, Clonal Heterogeneity, Therapeutic Resistance, Disease Progression

Key Genes

TET2, BAX, BCL2, DNMT3A, IDH1, FLT3

PAD Project

No

Analytes Assessed

InDels, Extracellular Protein

Sample Storage

Fresh Frozen

Sample Prep

Whole Cells

Sample Type

PBMC

Tissue / Organ

Bone Marrow Aspirates

Species

Human

Panel Used

Custom

Proof Point Demonstrated

Better than Bulk, Cell Identity, Clonality, Co-occurrence, Multi-omics
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