Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Research Institute Children's Cancer Center Hamburg, Hamburg and Dept. of Pediatric Oncology and Hematology, University Medical Center, Hamburg, Germany.
Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Biochim Biophys Acta Mol Cell Res. 2023 Jun;1870(5):119467. doi: 10.1016/j.bbamcr.2023.119467. Epub 2023 Mar 21.
Within the various subtypes of ALL, patients with a BCR-ABL-positive background as well as with a genetic change in the KMT2A gene have by far the worst survival probabilities. Interestingly, both subtypes are characterized by highly activated tyrosine kinases. SHIP1 serves as an important negative regulator of the PI3K/AKT signaling pathway, which is often constitutively activated in ALL. The protein expression of SHIP1 is decreased in most T-ALL and in some subgroups of B-ALL. In this study, we analyzed the expression of SHIP1 protein in detail in the context of groups with aberrant activated tyrosine kinases, namely BCR-ABL (Ph+) and Flt3 (KMT2A translocations). We demonstrate that constitutively activated Src kinases downstream of BCR-ABL and receptor tyrosine kinases reduce the SHIP1 expression in a SHIP1-Y1021 phosphorylated-dependent manner with subsequent ubiquitin marked proteasomal degradation. Inhibition of BCR-ABL (Imatinib), Flt3 (Quizartinib) or Src-Kinase-Family (Saracatinib) leads to significant reconstitution of SHIP1 protein expression. These results further support a functional role of SHIP1 as tumor suppressor protein and could be the basis for the establishment of a targeted therapy form.
在各种 ALL 亚型中，具有 BCR-ABL 阳性背景以及 KMT2A 基因突变的患者的生存概率迄今为止最差。有趣的是，这两种亚型都具有高度激活的酪氨酸激酶。SHIP1 是 PI3K/AKT 信号通路的重要负调节因子，该通路在 ALL 中通常持续激活。SHIP1 的蛋白表达在大多数 T-ALL 和一些 B-ALL 亚组中降低。在这项研究中，我们详细分析了具有异常激活的酪氨酸激酶的组（即 BCR-ABL（Ph+）和 Flt3（KMT2A 易位））中 SHIP1 蛋白的表达。我们证明，BCR-ABL 下游的组成性激活 Src 激酶和受体酪氨酸激酶以依赖于 SHIP1-Y1021 磷酸化的方式降低 SHIP1 表达，随后通过泛素标记的蛋白酶体降解。BCR-ABL（伊马替尼）、Flt3（Quizartinib）或 Src-激酶家族（Saracatinib）的抑制导致 SHIP1 蛋白表达的显著重建。这些结果进一步支持 SHIP1 作为肿瘤抑制蛋白的功能作用，并且可能是建立靶向治疗形式的基础。
