Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation
Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation
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DOI：
10.1038/s41388-019-0757-y
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发表时间：
2019-06-13
期刊：
影响因子：
8
通讯作者：
Mueller, Joerg P.
中科院分区：
文献类型：
--
作者：
Kresinsky, Anne;Schnoeder, Tina M.;Mueller, Joerg P.
受体酪氨酸激酶FLT3在髓系和淋巴系祖细胞中表达。25-30%的急性髓性白血病（AML）患者存在FLT3激活突变。最常见的是内部串联序列复制（ITD）导致组成FLT3-ITD激酶活性，信号质量改变，促进白血病细胞转化。在这里，我们观察到受体样蛋白酪氨酸磷酸酶（RPTP） CD45/Ptprc在FLT3信号传导中的减弱作用。这种丰富的RPTP的低水平表达与flt3 - itd阳性AML患者的不良预后相关。为了进一步了解Ptprc在体内对FLT3-ITD活性的调节作用，我们将Ptprc敲除小鼠与FLT3-ITD敲入小鼠杂交。在FLT3-ITD小鼠中，Ptprc基因失活导致寿命急剧缩短和严重单核细胞增多症的发展，b细胞发育受阻和贫血。骨髓增生性表型与髓外造血、脾肝肿大和器官结构的严重改变有关。表型改变与FLT3-ITD转化信号的增加有关，包括其下游靶标STAT5的激活。这些数据揭示了Ptprc在体内调节FLT3-ITD信号活动的能力。此外，组织病理学和计算机断层扫描（CT）显示了一个意想不到的骨表型；FLT3-ITD Ptprc（-/-）小鼠，但没有对照组，表现出骨形态的明显改变，部分表现出明显的骨质疏松症特征。在脾脏中，观察到异位骨形成。观察到的骨表型表明，FLT3- itd（可能是FLT3）在CD45/Ptprc负调控下调节骨发育/重塑的能力以前未被认识到。
The receptor tyrosine kinase FLT3 is expressed in myeloid and lymphoid progenitor cells. Activating mutations in FLT3 occur in 25-30% of acute myeloid leukaemia (AML) patients. Most common are internal tandem duplications of sequence (ITD) leading to constitutive FLT3-ITD kinase activity with an altered signalling quality promoting leukaemic cell transformation. Here, we observed the attenuating role of the receptor-like protein tyrosine phosphatase (RPTP) CD45/Ptprc in FLT3 signalling in vivo. Low level expression of this abundant RPTP correlates with a poor prognosis of FLT3-ITD-positive AML patients. To get a further insight into the regulatory role of Ptprc in FLT3-ITD activity in vivo, Ptprc knockout mice were bred with FLT3-ITD knock-in mice. Inactivation of the Ptprc gene in FLT3-ITD mice resulted in a drastically shortened life span and development of severe monocytosis, a block in B-cell development and anaemia. The myeloproliferative phenotype was associated with extramedullary haematopoiesis, splenohepatomegaly and severe alterations of organ structures. The phenotypic alterations were associated with increased transforming signalling of FLT3-ITD, including activation of its downstream target STAT5. These data reveal the capacity of Ptprc for the regulation of FLT3-ITD signalling activity in vivo. In addition, histopathology and computed tomography (CT) revealed an unexpected bone phenotype; the FLT3-ITD Ptprc(-/-) mice, but none of the controls, showed pronounced alterations in bone morphology and, in part, apparent features of osteoporosis. In the spleen, ectopic bone formation was observed. The observed bone phenotypes suggest a previously unappreciated capacity of FLT3-ITD (and presumably FLT3) to regulate bone development/remodelling, which is under negative control of CD45/Ptprc.