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

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.
Authors	Kirsteen J Campbell, Mary L Bath, Marian L Turner, Cassandra J Vandenberg, Philippe Bouillet, Donald Metcalf, Clare L Scott, Suzanne Cory
Journal	Blood (Blood) Vol. 116 Issue 17 Pg. 3197-207 (Oct 28 2010) ISSN: 1528-0020 [Electronic] United States
PMID	20631380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents, Alkylating Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Mcl1 protein, mouse Membrane Proteins Myc protein, mouse Myeloid Cell Leukemia Sequence 1 Protein Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-myc Cyclophosphamide
Topics	Animals Antineoplastic Agents, Alkylating (pharmacology, therapeutic use) Apoptosis Regulatory Proteins (metabolism) Autoimmunity Bcl-2-Like Protein 11 Cell Survival Cell Transformation, Neoplastic (genetics) Cyclophosphamide (pharmacology, therapeutic use) Drug Resistance, Neoplasm Hematopoiesis Hematopoietic Stem Cells (cytology, metabolism, pathology) Humans Lymphocytes (cytology, metabolism, pathology) Lymphoma (drug therapy, genetics, pathology) Lymphopoiesis Membrane Proteins (metabolism) Mice Mice, Inbred C57BL Mice, Transgenic Myeloid Cell Leukemia Sequence 1 Protein Myeloid Cells (cytology, metabolism, pathology) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism) Proto-Oncogene Proteins c-myc (metabolism) Up-Regulation

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