Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.
Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.
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PTPN 11编码涉及几种信号传导途径的Shp 2非受体蛋白酪氨酸磷酸酶。Shp 2的激活突变通常与青少年粒单核细胞白血病（JMML）相关，但在其他肿瘤中并不明确。在这里，我们报告了在ECOG E1900数据集中，Shp 2突变在人类急性髓性白血病（AML）中的发生率为6.6%（6/91）。我们研究了突变的Shp 2在携带MLL易位的白血病中的作用，MLL易位在人类AML中共同发生。通常在白血病患者中观察到的过度活跃的Shp 2 E76 K突变体显著加速了MLL-AF 9介导的体内白血病发生。Shp 2 E76 K增加白血病干细胞频率并提供MLL-AF 9白血病细胞IL 3细胞因子超敏性。由于Shp 2被报道调节抗凋亡基因，我们研究了在有和没有Shp 2 E76 K的MLL-AF 9白血病细胞中Bcl 2、Bcl-xL和Mcl 1的表达。虽然Bcl 2家族的基因在Shp 2 E76 K细胞中上调，但Mcl 1在MLL-AF 9细胞中响应于Shp 2 E76 K显示出最高的上调。事实上，Mcl 1在MLL-AF 9细胞中的表达与Shp 2 E76 K的表达表型相似，表明Shp 2突变通过激活抗凋亡基因而协同作用。最后，我们发现Shp 2 E76 K突变降低了AML细胞对小分子介导的Mcl 1抑制的敏感性，表明靶向Mcl 1的药物在Shp 2过度活跃患者中的疗效降低。
PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia (JMML) but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 dataset. We examined the role of mutated Shp2 in leukemias harboring MLL translocations which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9 mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. While the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small molecule mediated Mcl1 inhibition suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.
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