Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California-Santa Cruz, Santa Cruz, CA, USA.
Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California-Santa Cruz, Santa Cruz, CA, USA.
Exp Hematol. 2014 Mar;42(3):218-229.e4. doi: 10.1016/j.exphem.2013.11.013. Epub 2013 Dec 11.
Defining differentiation pathways is central to understanding the pathogenesis of hematopoietic disorders, including leukemia. The function of the receptor tyrosine kinase Flk2 (Flt3) in promoting myeloid development remains poorly defined, despite being commonly mutated in acute myeloid leukemia. We investigated the effect of Flk2 deficiency on myelopoiesis, focusing on specification of progenitors between HSC and mature cells. We provide evidence that Flk2 is critical for proliferative expansion of multipotent progenitors that are common precursors for all lymphoid and myeloid lineages, including megakaryocyte/erythroid (MegE) cells. Flk2 deficiency impaired the generation of both lymphoid and myeloid progenitors by abrogating propagation of their common upstream precursor. At steady state, downstream compensatory mechanisms masked the effect of Flk2 deficiency on mature myeloid output, whereas transplantation of purified progenitors revealed impaired generation of all mature lineages. Flk2 deficiency did not affect lineage choice, thus dissociating the role of Flk2 in promoting cell expansion and regulating cell fate. Surprisingly, despite impairing myeloid development, Flk2 deficiency afforded protection against myeloablative insult. This survival advantage was attributed to reduced cell cycling and proliferation of progenitors in Flk2-deficient mice. Our data support the existence of a common Flk2(+) intermediate for all hematopoietic lineages and provide insight into how activating Flk2 mutations promote hematopoietic malignancy by non-Flk2-expressing myeloid cells.
定义分化途径对于理解造血系统疾病的发病机制至关重要，包括白血病。尽管受体酪氨酸激酶 Flk2（Flt3）在急性髓系白血病中经常发生突变，但它在促进髓系发育中的作用仍未得到明确界定。我们研究了 Flk2 缺失对髓系发生的影响，重点关注 HSC 和成熟细胞之间祖细胞的特化。我们提供的证据表明，Flk2 对于多能祖细胞的增殖扩张至关重要，这些祖细胞是所有淋巴和髓系谱系的常见前体，包括巨核细胞/红细胞（MegE）细胞。Flk2 缺失通过阻断其共同上游前体的增殖来损害淋巴系和髓系祖细胞的生成。在稳定状态下，下游补偿机制掩盖了 Flk2 缺失对成熟髓系输出的影响，而移植纯化的祖细胞则揭示了所有成熟谱系生成受损。Flk2 缺失不影响谱系选择，因此将 Flk2 在促进细胞扩张和调节细胞命运中的作用区分开来。令人惊讶的是，尽管 Flk2 缺失会损害髓系发育，但它为骨髓清除性损伤提供了保护。这种生存优势归因于 Flk2 缺失小鼠中祖细胞的细胞周期和增殖减少。我们的数据支持所有造血谱系存在共同的 Flk2(+)中间产物，并深入了解激活的 Flk2 突变如何通过非 Flk2 表达的髓系细胞促进造血恶性肿瘤。
