Abstract
CBFβ-SMMHC is expressed in 8% of acute myeloid leukemias and inhibits AML1/RUNX1. In this study, murine marrow or human CD34+ cells were transduced with retroviral or lentiviral vectors expressing CBFβ-SMMHC or two mutant variants. CBFβ-SMMHC reduced murine or human myeloid cell proliferation three- to four-fold in liquid culture relative to empty vector-transduced cells, during a period when vector-transduced cells accumulated five-fold and human cells 20-fold. CBFβ-SMMHC decreased the formation of myeloid, but not erythroid, colonies two- to four-fold, and myeloid colonies expressing CBFβ-SMMHC were markedly reduced in size. However, CBFβ-SMMHC did not slow differentiation to granulocytes or monocytes. Neither CBFβ-SMMHC(Δ2–11), which does not bind AML1, nor CBFβ-SMMHC(ΔACD), which does not multimerize or efficiently bind corepressors, slowed proliferation or reduced myeloid colonies. CBFβ-SMMHC increased the G1/S ratio 1.4-fold. AML1 had an effect opposite to CBFβ-SMMHC, stimulating proliferation of murine myeloid progenitors 2.0-fold in liquid culture. Thus, CBFβ-SMMHC directly inhibits the proliferation of normal myeloid progenitors via inhibition of AML1 and dependent upon the integrity of its assembly competence domain. These findings support the development of therapeutics that target the ability of CBFβ-SMMHC to interact with AML1 or to multimerize via its assembly competence domain.
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Acknowledgements
We thank M Barbacid and A Pellicer for p15(−/−) mice and D Wang for the method of isolation of puromycin-selected myeloid progenitors. This work was supported by grants from NIH (R01 CA098805) and the Children's Cancer Foundation to ADF and a Fellow Award from the National Foundation for Cancer Research to CIC. Financial disclosure: The Johns Hopkins University holds patents on CD34 monoclonal antibodies and inventions related to stem cells. Dr Civin is entitled to a share of the sales royalty received by the University under licensing agreements between the University, Becton Dickinson Corporation, and Baxter HealthCare Corporation. Dr Civin is a paid consultant to Becton Dickinson Corporation. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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D'Costa, J., Chaudhuri, S., Civin, C. et al. CBFβ-SMMHC slows proliferation of primary murine and human myeloid progenitors. Leukemia 19, 921–929 (2005). https://doi.org/10.1038/sj.leu.2403755
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DOI: https://doi.org/10.1038/sj.leu.2403755