Division of Hematology, Department of Internal Medicine.
Clara D. Bloomfield Center for Leukemia Outcomes Research, and.
Blood Adv. 2022 Mar 8;6(5):1371-1380. doi: 10.1182/bloodadvances.2021006242.
Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).
与急性髓系白血病（AML）患者化疗结果相关的预后因素已有广泛报道，其中一个基因的突变被认为对几种新型靶向治疗具有耐药性，该基因为蛋白酪氨酸磷酸酶非受体型 11（PTPN11）。PTPN11 突变在 AML 中的更广泛临床意义仍未被很好地理解。本研究的目的是确定 PTPN11 突变与哪些细胞遗传学异常和基因突变共同发生，以及 PTPN11 突变如何影响接受强化化疗的患者的结局。我们研究了新诊断为 AML（不包括急性早幼粒细胞白血病）的 1725 例患者（不包括急性早幼粒细胞白血病），这些患者入组了癌症和白血病组 B/肿瘤临床研究联盟试验。在 140 例 PTPN11 突变患者样本中，PTPN11 最常与 NPM1、DNMT3A 和 TET2 突变共同发生。PTPN11 突变在具有 inv(3)(q21q26)/t(3;3)(q21;q26)和正常核型的患者中相对常见，但在具有典型复杂核型和核心结合因子 AML 的患者中非常罕见。PTPN11 突变位于 N 端 SH2 结构域与磷酸酶结构域比，早期死亡率更高。PTPN11 突变不影响 NPM1 突变患者的结局，但这些患者不太可能存在共同的激酶突变（即 FLT3-ITD），这表明重叠信号通路的激活。然而，在 NPM1 野生型 AML 患者中，PTPN11 突变与不良患者结局相关，为研究该分子亚组的生物学和治疗方法提供了依据。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT00048958（CALGB 8461）、#NCT00899223（CALGB 9665）和 #NCT00900224（CALGB 20202）。
