Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance.
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.
Campbell
Kirsteen J
KJ
Molecular Genetics of CancerDivision, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Victoria, Australia.
Bath
Mary L
ML
Turner
Marian L
ML
Vandenberg
Cassandra J
CJ
Bouillet
Philippe
P
Metcalf
Donald
D
Scott
Clare L
CL
Cory
Suzanne
S
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015854:Up-Regulation
D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; C489428:Myc protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D003520:Cyclophosphamide