BCL-xL Degrader DT2216 Is Effective in JAK2-Mutated AML Post-MPN Models

DT2216, in combination with 5-azacitidine (AZA), ruxolitinib, or MCL-1 inhibitor S63845, showed promising efficacy in JAK2 mutant acute myeloid leukemia (AML) post-myeloproliferative neoplasms (MPN) models, according to a recent analysis.

The combination demonstrated reduced cell viability, on-target degradation of B-cell lymphoma-extra large (BCL-xL), and synergistic anti-leukemia effects in JAK2 mutant AML.

Zhe Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues performed clonogenic assays with three distinct JAK2 mutant AML patient samples to assess the anti-leukemia effects on hematopoietic stem and progenitor cells (HSPCs). They also used western blot to determine BCL-xL degradation and measure the expression of BCL-2 and MCL-1 after treatment.

At 72 hours, the average combination index (CI) values for DT2216 plus S68425, DT2216 plus AZA, and DT2216 plus ruxolitinib were 0.13, 0.17, and 0.36, respectively. DT2216 as a single agent also significantly reduced cell viability in JAK2 mutant AML cell lines, with an average half maximal inhibitory concentration of 1.61 μM in parental cell lines and 5.37 μM in ruxolitinib-resistant cell lines at 72 hours.

Clonogenic assays showed a 69% reduction in colony count with DT2216 treatment alone and a 76% reduction with the combination of DT2216 (50 nM) plus AZA (100 nM). Meanwhile, western blot analysis showed average BCL-xL reductions of 78.5%, 82.75%, and 86.75% after 24 hours of treatment with DT2216 alone or in combination with AZA or ruxolitinib.

“These results provide valuable insights into future therapeutic strategies for the treatment of JAK2-mut AML, particularly in the context of post-MPN AML,” the researchers concluded.

Reference

Wang Z, Zhang Q, Skwarska S, et al. Targeting BCL-XL with a novel VHL-based BCL-XL degrader DT-2216 in pre-clinical JAK2-mutant AML post-MPN models. Abstract #4154. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.