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Targeting anti‐apoptotic BCL 2 family proteins in haematological malignancies – from pathogenesis to treatment
Author(s) -
Vogler Meike,
Walter Harriet S.,
Dyer Martin J. S.
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14684
Subject(s) - venetoclax , mcl1 , chronic lymphocytic leukemia , pathogenesis , lymphoma , cancer research , myeloid , immunology , biology , apoptosis , leukemia , medicine , downregulation and upregulation , genetics , gene
Summary The B‐cell lymphoma 2 ( BCL 2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL 2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti‐apoptotic functions of BCL 2 proteins using structure‐based design to produce specific inhibitors of protein–protein interactions has been achieved for BCL 2, MCL 1 and BCL ‐ X L (also termed BCL 2L1), providing an armamentarium of new targeted therapies called BH 3‐mimetics. The first BCL 2‐specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia ( CLL ), with surprisingly little toxicity given the expression of BCL 2 in normal tissues. Despite success in CLL , where sensitivity to BCL 2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B‐cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL 2 inhibition. In this review, we summarise the biology of BCL 2 proteins, the mechanism of action of BH 3‐mimetics and the status of their clinical development in haematological malignancies.