The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies. Activating mutations in PTPN11 increase downstream proliferative signaling and cell survival. We investigated the signaling upstream of PTPN11 in JMML and AML cells and found that PTPN11 was activated by the nonreceptor tyrosine/serine/threonine kinase TNK2 and that PTPN11-mutant JMML and AML cells were sensitive to TNK2 inhibition. In cultured human cell–based assays, PTPN11 and TNK2 interacted directly, enabling TNK2 to phosphorylate PTPN11, which subsequently dephosphorylated TNK2 in a negative feedback loop. Mutations in PTPN11 did not affect this physical interaction but increased the basal activity of PTPN11 such that TNK2-mediated activation was additive. Consequently, coexpression of TNK2 and mutant PTPN11 synergistically increased mitogen-activated protein kinase (MAPK) signaling and enhanced colony formation in bone marrow cells from mice. Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11-mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib. Together, these data suggest that TNK2 is a promising therapeutic target for PTPN11-mutant leukemias.

酪氨酸磷酸酶PTPN11蛋白与青少年骨髓单核细胞白血病（JMML），急性髓细胞性白血病（AML）和其他恶性肿瘤的发病机制有关。PTPN11中的激活突变可增加下游增殖信号和细胞存活率。我们研究了JMML和AML细胞中PTPN11的上游信号传导，发现PTPN11被非受体酪氨酸/丝氨酸/苏氨酸激酶TNK2激活，并且PTPN11突变的JMML和AML细胞对TNK2抑制敏感。在基于人类细胞的培养实验中，PTPN11和TNK2直接相互作用，使TNK2磷酸化PTPN11，随后在负反馈回路中将TNK2磷酸化。PTPN11中的突变不会影响这种物理相互作用，但会增加PTPN11的基础活性，因此TNK2介导的激活是加和的。所以，TNK2和突变体PTPN11的共表达协同增加了小鼠骨髓细胞中的促分裂原活化蛋白激酶（MAPK）信号传导并增强了集落形成。TNK2的化学抑制作用在体外用多激酶（包括TNK2）抑制剂达沙替尼治疗了PTPN11突变型JMML患者，从而在体外阻断了MAPK信号传导和集落形成，并减轻了疾病负担。总之，这些数据表明，TNK2是PTPN11突变型白血病的有希望的治疗靶标。TNK2的化学抑制作用在体外用多激酶（包括TNK2）抑制剂达沙替尼治疗了PTPN11突变的JMML患者，从而在体外阻断了MAPK信号传导和集落形成，并减轻了疾病负担。总之，这些数据表明，TNK2是PTPN11突变型白血病的有希望的治疗靶标。TNK2的化学抑制作用在体外用多激酶（包括TNK2）抑制剂达沙替尼治疗了PTPN11突变型JMML患者，从而在体外阻断了MAPK信号传导和集落形成，并减轻了疾病负担。总之，这些数据表明，TNK2是PTPN11突变型白血病的有希望的治疗靶标。