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

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.
ALL; Asciminib; BCL-2; CML; Nilotinib; Venetoclax
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/406267
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