Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Blood. 2011 Feb 24;117(8):2460-8. doi: 10.1182/blood-2010-08-300087. Epub 2010 Dec 29.
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.
RARA（维甲酸受体α）单倍不足是急性早幼粒细胞白血病（APL）中 t（15；17）（q22；q21）易位的必然结果。视黄酸和 RARA 活性已被牵连到造血自我更新和中性粒细胞成熟中。因此，我们和其他人预测 RARA 单倍不足会导致 APL 的发病机制。为了验证这一假设，我们将 Rara(+/-) 小鼠与在组织蛋白酶 G 基因座（mCG-PR）表达 PML（早幼粒细胞白血病）-RARA 的小鼠进行杂交。我们发现 Rara 单倍不足与 PML-RARA 合作，但仅适度影响前白血病和白血病表型。mCG-PR(+/-)×Rara(+/-) 小鼠的骨髓中成熟髓细胞数量减少，体外髓细胞增殖增加，移植后竞争优势增加。Rara 单倍不足不会改变 mCG-PR 依赖性白血病潜伏期或穿透性，但会影响白血病细胞的分布；mCG-PR(+/-)×Rara(+/-) 小鼠中的白血病更常见于白细胞计数低至正常和淋巴结的髓样浸润。这些小鼠的 APL 细胞对全反式视黄酸有反应，与在 mCG-PR(+/-)×Rara(+/+) 小鼠中发生的肿瘤相比，其表达谱几乎没有差异。这些数据表明，Rara 单倍不足（与 Pml 单倍不足和 RARA-PML 一样）可以与 PML-RARA 合作，影响小鼠中 APL 的发病机制，但 PML-RARA 是 t（15；17）疾病起始突变。
