title: Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice.
abstract: RARA (retinoic acid receptor alpha) haploinsufficiency is an invariable consequence of t(15;17)(q22;q21) translocations in acute promyelocytic leukemia (APL). Retinoids and RARA activity have been implicated in hematopoietic self-renewal and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis, we crossed Rara(+/-) mice with mice expressing PML (promyelocytic leukemia)-RARA from the cathepsin G locus (mCG-PR). We found that Rara haploinsufficiency cooperated with PML-RARA, but only modestly influenced the preleukemic and leukemic phenotype. Bone marrow from mCG-PR(+/-) × Rara(+/-) mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation, and increased competitive advantage after transplantation. Rara haploinsufficiency did not alter mCG-PR-dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; leukemia in mCG-PR(+/-) × Rara(+/-) mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL cells from these mice were responsive to all-trans retinoic acid and had virtually no differences in expression profiling compared with tumors arising in mCG-PR(+/-) × Rara(+/+) mice. These data show that Rara haploinsufficiency (like Pml haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis of APL in mice, but that PML-RARA is the t(15;17) disease-initiating mutation.
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.forename: Nobish
authors.initials: N
authors.lastname: Varghese
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D020869:Gene Expression Profiling; D057895:Haploinsufficiency / Q000502:physiology*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha
chemical_list: D015514:Oncogene Proteins, Fusion; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein