Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary.
Pathol Oncol Res. 2024 Jul 5;30:1611747. doi: 10.3389/pore.2024.1611747. eCollection 2024.
Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30 G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.
视网膜母细胞瘤（Rb）蛋白、Akt 激酶和 Erk 激酶（细胞外信号调节激酶）的信号通路在急性髓细胞白血病的发病机制中具有重要作用。这些蛋白质通过磷酸化的组成性激活通过调节细胞周期、增殖和促凋亡信号转导过程来促进细胞存活。根据先前的数据，这些蛋白质的磷酸化形式代表癌症患者预后较差。我们使用磷酸化特异性抗体通过 Western blot 技术在 69 例 AML 患者、36 例骨髓增生异常综合征（MDS）患者和 10 名健康志愿者的骨髓或外周血样本中检测了磷酸化 Rb（P-Rb）、Akt（P-Akt）和 Erk（P-Erk）蛋白的存在。还检查了 Akt 激酶途径的负调节剂 PTEN（磷酸酶和张力蛋白同源物）和 PHLPP（PH 结构域和富含亮氨酸重复蛋白磷酸酶）磷酸酶的表达水平。我们测试了这些蛋白质对 AML 患者生存的影响及其与已知预后特征的相关性。我们发现 46.3%的 AML 患者可检测到 P-Rb，34.7%的患者有 P-Akt，28.9%的患者有 P-Erk 蛋白。表达 PTEN 的患者为 66.1%，表达 PHLPP 的患者为 38.9%，同时表达 PTEN 和 PHLPP 的患者为 37.2%，既不表达 PTEN 也不表达 PHLPP 的患者为 32.2%。与核磷蛋白突变（NPMc）阴性样本相比，核磷蛋白突变患者的 P-Erk 明显减少，诊断时外周白细胞计数超过 30×10^9/L 的患者的 P-Rb 明显减少。在 FAB 类型 M5 中，PHLPP 明显存在。P-Rb 的表达与总生存期（OS）显著相关，而在不利核型患者中，P-Akt 与无事件生存期（EFS）显著相关。同时存在 PHLPP 和 PTEN 磷酸酶有助于改善 OS 和 EFS，尽管差异无统计学意义。我们证实 P-Akt 与 PHLPP 之间存在显著正相关。评估 Rb、Akt 和 Erk 的磷酸化可能会确定一组特别受益于新的靶向治疗选择的 AML 患者，补充标准化疗，并有助于监测 AML 的缓解、复发或进展。
