Chen L, Chen W, Mysliwski M, Serio J, Ropa J, Abulwerdi F A, Chan R J, Patel J P, Tallman M S, Paietta E, Melnick A, Levine R L, Abdel-Wahab O, Nikolovska-Coleska Z, Muntean A G
1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Leukemia. 2015 Jun;29(6):1290-300. doi: 10.1038/leu.2015.18. Epub 2015 Feb 4.
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 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 data set. 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. Although 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.
PTPN11编码参与多种信号通路的Shp2非受体蛋白酪氨酸磷酸酶。Shp2中的激活突变通常与青少年骨髓单核细胞白血病相关，但在其他肿瘤中尚未明确界定。在此我们报告，在ECOG E1900数据集中，人类急性髓系白血病（AML）中Shp2突变的发生率为6.6%（6/91）。我们研究了突变的Shp2在伴有MLL易位的白血病中的作用，MLL易位在人类AML中同时出现。在白血病患者中常见的高活性Shp2E76K突变体在体内显著加速了MLL-AF9介导的白血病发生。Shp2E76K增加了白血病干细胞频率，并使MLL-AF9白血病细胞对IL3细胞因子超敏感。由于据报道Shp2调节抗凋亡基因，我们研究了有或没有Shp2E76K的MLL-AF9白血病细胞中Bcl2、Bcl-xL和Mcl1的表达。尽管在Shp2E76K细胞中Bcl2基因家族上调，但在MLL-AF9细胞中，Mcl1对Shp2E76K的反应上调最为明显。事实上，MLL-AF9细胞中Mcl1的表达模拟了Shp2E76K的表达，表明Shp2突变通过激活抗凋亡基因发挥协同作用。最后，我们表明Shp2E76K突变降低了AML细胞对小分子介导的Mcl1抑制的敏感性，这表明在Shp2活性过高的患者中，靶向MCL1的药物疗效降低。
