Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival.
The Akt kinases promote hematopoietic cell growth and accumulation through phosphorylation of apoptotic effectors and stimulation of mTOR-dependent translation. In Akt-transformed leukemic cells, tumor growth can be inhibited by the mTOR inhibitor rapamycin, and clinical trials of rapamycin analogs for the treatment of leukemia are under way. Surprisingly, nontransformed hematopoietic cells can grow and proliferate in the presence of rapamycin. Here, we show that Pim-2 is required to confer rapamycin resistance. Primary hematopoietic cells from Pim-2- and Pim-1/Pim-2-deficient animals failed to accumulate and underwent apoptosis in the presence of rapamycin. Although animals deficient in Akt-1 or Pim-1/Pim-2 are viable, few animals with a compound deletion survived development, and those that were born had severe anemia. Primary hematopoietic cells from Akt-1/Pim-1/Pim-2-deficient animals displayed marked impairments in cell growth and survival. Conversely, ectopic expression of either Pim-2 or Akt-1 induced increased cell size and apoptotic resistance. However, though the effects of ectopic Akt-1 were reversed by rapamycin or a nonphosphorylatable form of 4EBP-1, those of Pim-2 were not. Coexpression of the transgenes in mice led to additive increases in cell size and survival and predisposed animals to rapid tumor formation. Together, these data indicate that Pim-2 and Akt-1 are critical components of overlapping but independent pathways, either of which is sufficient to promote the growth and survival of nontransformed hematopoietic cells.
Hammerman
Peter S
PS
Department of Cancer Biology and Abramson Family Cancer Research Institute, Rm 451 BRB II/III, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Fox
Casey J
CJ
Birnbaum
Morris J
MJ
Thompson
Craig B
CB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000209:etiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D020123:Sirolimus / Q000494:pharmacology; D014161:Transduction, Genetic
D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D020123:Sirolimus