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

KJ Campbell, ML Bath, ML Turner… - Blood, The Journal …, 2010 - ashpublications.org
KJ Campbell, ML Bath, ML Turner, CJ Vandenberg, P Bouillet, D Metcalf, CL Scott, S Cory
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
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/ Eμ-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 Eμ-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.
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