Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice

John S. Welch, Jeffery M. Klco, Nobish Varghese, Rakesh Nagarajan, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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+/- x 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 mCGPR-dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; leukemia in mCG-PR+/- x 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+/- x 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.

Original languageEnglish
Pages (from-to)2460-2468
Number of pages9
JournalBlood
Volume117
Issue number8
DOIs
StatePublished - Feb 24 2011

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