Constitutive HOXA5 expression inhibits erythropoiesis and increases myelopoiesis from human hematopoietic progenitors
Constitutive HOXA5 expression inhibits erythropoiesis and increases myelopoiesis from human hematopoietic progenitors
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DOI：
10.1182/blood.v94.2.519.414k20_519_528
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发表时间：
1999-07-15
期刊：
影响因子：
20.3
通讯作者：
Gasson, JC
中科院分区：
文献类型：
--
作者：
Crooks, GM;Fuller, J;Gasson, JC
通过在骨髓和脐带血的CD 34（+）和CD 34（+）CD 38（-）细胞中组成型表达HOXA 5 cDNA，研究了HOXA 5在正常人造血中的作用。通过使用含有HOXA 5和细胞表面标记基因的逆转录病毒载体，获得表达转基因的纯祖细胞群体用于分化模式的分析。基于对来自转导的CD 34（+）细胞的培养物的免疫表型和形态学分析，与用对照载体转导的CD 34（+）细胞相比，HOXA 5表达导致向髓系分化和远离红系分化的显著转变（对于免疫表型分析，P = .001，n = 15;对于形态学分析，P < .0001，n = 19）。转导更多的原始祖细胞（CD 34（+）CD 38（-）细胞）比转导大量定型的CD 34（+）细胞对分化的影响显著更大（HOXA 5对CD 34（+）v CD 34（+）CD 38（-）细胞的影响差异P = 0.006）。在用HOXA 5载体转导的祖细胞中，红系祖细胞（爆发形成单位-红系[BFU-E]）的频率显著降低（P = 0.016，n = 7），而总CFU数没有减少。用HOXA 5或对照载体（在红系培养条件下培养）转导的单细胞的克隆分析显示，HOXA 5表达阻止红系分化并产生具有未分化胚细胞优势的克隆。这些研究表明HOXA 5的组成型表达抑制人红细胞生成并促进骨髓生成。在不存在任何可证实的对增殖的作用的情况下，红细胞生成的相互抑制和骨髓生成的促进表明HOXA 5使多能祖细胞阶段的分化从红细胞转向骨髓途径。(C)1999年，美国血液学会。
The role of the homeobox gene HOXA5 in normal human hematopoiesis was studied by constitutively expressing the HOXA5 cDNA in CD34(+) and CD34(+)CD38(-) cells from bone marrow and cord blood. By using retroviral vectors that contained both HOXA5 and a cell surface marker gene, pure populations of progenitors that expressed the transgene were obtained for analysis of differentiation patterns. Based on both immunophenotypic and morphological analysis of cultures from transduced CD34(+) cells, HOXA5 expression caused a significant shift toward myeloid differentiation and away from erythroid differentiation in comparison to CD34(+) cells transduced with Control vectors (P = .001, n = 15 for immunophenotypic analysis; and P < .0001, n = 19 for morphological analysis). Transduction of more primitive progenitors (CD34(+)CD38(-) cells) resulted in a significantly greater effect on differentiation than did transduction of the largely committed CD34(+) population (P = .006 for difference between HOXA5 effect on CD34(+) v CD34(+)CD38(-) cells). Erythroid progenitors (burst-forming unit-erythroid [BFU-E]) were significantly decreased in frequency among progenitors transduced with the HOXA5 vector (P = .016, n = 7), with no reduction in total CFU numbers. Clonal analysis of single cells transduced with HOXA5 or control vectors (cultured in erythroid culture conditions) showed that HOXA5 expression prevented erythroid differentiation and produced clones with a preponderance of undifferentiated blasts. These studies show that constitutive expression of HOXA5 inhibits human erythropoiesis and promotes myelopoiesis. The reciprocal inhibition of erythropoiesis and promotion of myelopoiesis in the absence of any demonstrable effect on proliferation suggests that HOXA5 diverts differentiation at a mulitpotent progenitor stage away from the erythroid toward the myeloid pathway. (C) 1999 by The American Society of Hematology.