Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Campbell, KJ; Bath, ML; Turner, ML; Vandenberg, CJ; Bouillet, P; Metcalf, D; Scott, CL; Cory, S

Author(s): Campbell, KJ; Bath, ML; Turner, ML; Vandenberg, CJ; Bouillet, P; Metcalf, D; Scott, CL; Cory, S;
Details: Publication Year 2010-10-28,Volume 116,Issue #17,Page 3197-3207
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ E mu-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from (Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional E mu-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells. (Blood. 2010; 116(17):3197-3207)
Publisher: AMER SOC HEMATOLOGY
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995351/
Publisher's Version: https://doi.org/10.1182/blood-2010-04-281071
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-10-28 12:00:00

Last Modified: 2014-12-23 12:08:51