A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency.
Myeloproliferative syndromes (MPS) are a heterogeneous subclass of nonlymphoid hematopoietic neoplasms which are considered to be intrinsic to hematopoietic cells. The causes of MPS are largely unknown. Here, we demonstrate that mice deficient for retinoic acid receptor gamma (RARgamma), develop MPS induced solely by the RARgamma-deficient microenvironment. RARgamma(-/-) mice had significantly increased granulocyte/macrophage progenitors and granulocytes in bone marrow (BM), peripheral blood, and spleen. The MPS phenotype continued for the lifespan of the mice and was more pronounced in older mice. Unexpectedly, transplant studies revealed this disease was not intrinsic to the hematopoietic cells. BM from wild-type mice transplanted into mice with an RARgamma(-/-) microenvironment rapidly developed the MPS, which was partially caused by significantly elevated TNFalpha in RARgamma(-/-) mice. These data show that loss of RARgamma results in a nonhematopoietic cell-intrinsic MPS, revealing the capability of the microenvironment to be the sole cause of hematopoietic disorders.
Walkley
Carl R
CR
Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia.
Olsen
Gemma Haines
GH
Dworkin
Sebastian
S
Fabb
Stewart A
SA
Swann
Jeremy
J
McArthur
Grant A
GA
Westmoreland
Susan V
SV
Chambon
Pierre
P
Scadden
David T
DT
Purton
Louise E
LE
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D017690:Cell Transplantation; D006098:Granulocytes / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D000097768:Retinoic Acid Receptor gamma
D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma