BH3 Mimetics Augment Cytotoxic T Cell Killing of Acute Myeloid Leukemia via Mitochondrial Apoptotic Mechanism.

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins.

Nontransplant treatment approaches for myeloid neoplasm with mutated TP53.

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a challenging spectrum of clonal myeloid disease with poor prognosis. Recent studies have shown that in AML, MDS, and MDS/AML with biallelic TP53 loss, the TP53-mutated clone becomes dominant. These are highly aggressive diseases that are resistant to most chemotherapies.

BCL2i-Based Therapies and Emerging Resistance in Chronic Lymphocytic Leukemia.

Overexpression of the anti-apoptotic protein BCL-2 is a key factor in the pathogenesis of chronic lymphocytic leukemia (CLL) and is associated with poor clinical outcomes. Therapeutic activation of apoptosis in cancer cells using the BCL-2 inhibitor (BCL2i) venetoclax has shown remarkable efficacy in clinical trials, both as monotherapy and combination regimens. However, patients with CLL experience a highly variable clinical course, facing significant challenges in advanced stages due to disease relapse and the emergence of resistant clones.

Anti-leukemia efficacy of the dual BCL2/BCL-XL inhibitor AZD0466 in acute lymphoblastic leukemia preclinical models.

The upregulation of BCL2 and BCL-XL, two proteins in the BCL2 family of proteins, leads to a disproportional expression of pro-death and pro-survival proteins in favor of leukemia survival, tumorigenesis, and chemoresistance. In different subsets of acute lymphoblastic leukemia (ALL), the proportion of these two proteins varies, and their potential as therapeutic targets needs detailed characterization. Here, we investigated BCL2 and BCL-XL, the genes that encode BCL2 and BCL-XL, and their expression differences between B-cell acute lymphoblastic leukemia (B-ALL) and T-cell ALL (T-ALL).