Background/Aim: Philadelphia-positive acute lymphoblastic leukemia (Ph+ B-ALL) is caused by the malignant transformation of lymphoid cells induced by BCRABL1 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+ BALL 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.
Targeting BCL-2 as a therapeutic strategy for primary p210BCR-ABL1-positive B-ALL cells
Massimino M.Membro del Collaboration Group
;Tirro E.;Stella S.Membro del Collaboration Group
;Pennisi M. S.Membro del Collaboration Group
;Vitale S. R.Membro del Collaboration Group
;Puma A.Membro del Collaboration Group
;Manzella L.
2020-01-01
Abstract
Background/Aim: Philadelphia-positive acute lymphoblastic leukemia (Ph+ B-ALL) is caused by the malignant transformation of lymphoid cells induced by BCRABL1 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+ BALL 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.File | Dimensione | Formato | |
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