Journal
BLOOD
Volume 132, Issue 15, Pages 1573-1583Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-06-859405
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Funding
- Australian National Health and Medical Research Council [1145728, 1143105, 1086291, 1016701, 1020363]
- Leukemia & Lymphoma Society of America [LLS SCOR 7001-13]
- Cancer Council of Victoria [1086157, 1147328, 1052309]
- Victorian Cancer Agency fellowship [MCRF17028]
- Leukaemia Foundation Postgraduate Award
- Servier
- Craig Perkins Cancer Research Foundation
- Australian Government Independent Research Institute Infrastructure Support Scheme [9000220]
- Victorian State Government Operational Infrastructure Support Program
- Cancer Council of Victoria (Venture Grant)
- National Health and Medical Research Council of Australia [1145728, 1143105] Funding Source: NHMRC
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Myeloid cell leukemia-1 (MCL-1) is a prosurvival B-cell lymphoma 2 (BCL-2) family member required for the sustained growth of many cancers. Recently, a highly specific MCL-1 inhibitor, S63845, showing sixfold higher affinity to human compared with mouse MCL-1, has been described. To accurately test efficacy and tolerability of this BH3-mimetic (BH3-only protein mimetic) drug in preclinical cancer models, we developed a humanized Mcl-1 (huMcl-1) mouse strain in which MCL-1 was replaced with its human homolog. huMcl-1 mice are phenotypically indistinguishable from wild-type mice but are more sensitive to the MCL-1 inhibitor S63845. Importantly, nontransformed cells and lymphomas from huMcl-1; E mu-Myc mice are more sensitive to S63845 in vitro than their control counterparts. When huMcl-7;E mu-Myc lymphoma cells were transplanted into huMcl-1 mice, treatment with S63845 alone or alongside cyclophosphamide led to long-term remission in similar to 60% or almost 1 100% of mice, respectively. These results demonstrate the potential of our huMcl-1 mouse model for testing MCL-1 inhibitors, allowing precise predictions of efficacy and tolerability for clinical translation.
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