Targeting BCL-2 as a Therapeutic Strategy for Primary p210BCR-ABL1-positive B-ALL Cells

Abstract

Background/aim: Philadelphia-positive acute lymphoblastic leukemia (Ph⁺ B-ALL) is caused by the malignant transformation of lymphoid cells induced by BCR-ABL1 constitutive catalytic activity. BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML) cells, inducing durable hematological, cytogenetic and molecular responses. However, in Ph⁺ B-ALL - as in CML progressing to blast crisis - TKIs fail to maintain disease remission. We, therefore, wanted to investigate if dual targeting of BCL-2 and BCR-ABL1 would be more effective in killing Ph⁺ B-ALL cells.

Materials and methods: p210-B-ALL CD34-positive cells were used to evaluate the BCR-ABL expression and pharmacological targeting of BCL-2, by venetoclax, alone or in combination with BCR-ABL1 inhibition.

Results: We demonstrated the cytotoxic effect of BCL-2 inhibition and that dual targeting of BCL-2 and BCR-ABL1 with venetoclax and nilotinib further increases this cytotoxicity.

Conclusion: BCL-2 is a key survival factor for primary Ph⁺ B-ALL cells and its inhibition - alone or in combination with a BCR-ABL1 TKI - should be further investigated as a potential therapeutic strategy for these patients.

Keywords: ALL; BCL-2; CML; asciminib; nilotinib; venetoclax.