Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
复制标题
DOI：
10.1182/blood-2010-06-289207
复制
发表时间：
2011-09-29
期刊：
影响因子：
20.3
通讯作者：
Jacobsen, Sten Eirik W.
中科院分区：
文献类型：
--
作者：
Kharazi, Shabnam;Mead, Adam J.;Jacobsen, Sten Eirik W.
获得纯合活化生长因子受体突变可能通过简单的基因剂量效应加速癌症进展。FLT 3的内部串联重复（ITD）发生在大约25%的急性髓性白血病病例中，并诱导配体非依赖性组成性信号传导。纯合子FLT 3-ITD预后不良，经常在复发时检测到。使用Flt 3-内部串联重复（Flt 3-ITD）诱导的骨髓增殖的小鼠敲入模型，我们在此证明，在Flt 3-ITD纯合小鼠中，粒细胞-单核细胞和原始Lin（-）Sca 1（+）c-Kit（+）祖细胞的增强的骨髓表型和扩增可以部分地通过第二个野生型等位基因的丢失来介导。此外，尽管自分泌FLT 3配体的产生与FLT 3-ITD骨髓恶性肿瘤和对FLT 3抑制剂的耐药性有关，但我们在此证明小鼠FLT 3（ITD/ITD）骨髓表型是FLT 3配体非依赖性的。（血。2011; 118（13）：3613-3621）
Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent. (Blood. 2011; 118(13):3613-3621)