Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Princess Margaret Cancer Center, Toronto, Ontario, Canada.
Leukemia. 2018 Jan;32(1):203-213. doi: 10.1038/leu.2017.250. Epub 2017 Aug 14.
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation models for CML and BCR-ABL1 B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1 B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, are essential for BCR-ABL1, but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (ERK) pathway is regulated by SHP2 in WT and BCR-ABL1 pre-B cells, but is only required for the proliferation of BCR-ABL1 cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1 pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1 and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.
BCR-ABL1 靶向酪氨酸激酶抑制剂 (TKI) 彻底改变了费城染色体阳性 (Ph) 血液肿瘤的治疗方法。然而，获得性 TKI 耐药仍然是慢性髓细胞白血病 (CML) 的一个主要问题，并且 TKI 对 Ph B 细胞急性淋巴细胞白血病 (B-ALL) 的疗效较差。GAB2 是一种支架衔接蛋白，可与 SHP2 结合并激活 SHP2，对于 BCR-ABL1 诱导的白血病发生至关重要，并且缺乏与 SHP2 结合的 GAB2 突变体不能介导白血病发生。我们使用遗传功能丧失方法和 CML 和 BCR-ABL1 B-ALL 的骨髓移植模型，表明 SHP2 是 BCR-ABL1 诱导的髓系和淋巴肿瘤所必需的。Ptpn11 缺失会损害 CML 样骨髓增生性肿瘤的起始和维持，并损害 BCR-ABL1 B-ALL 的诱导。SHP2，特别是其 SH2 结构域、PTP 活性和 C 末端酪氨酸，对于 BCR-ABL1 但不是 WT 前 B 细胞的增殖是必不可少的。丝裂原活化蛋白激酶激酶 (MEK)/细胞外信号调节激酶 (ERK) 途径在 WT 和 BCR-ABL1 前 B 细胞中受 SHP2 调节，但仅在前 BCR-ABL1 细胞的增殖中需要。SHP2 仅在前 BCR-ABL1 前 B 细胞中需要 SRC 家族激酶 (SFK) 的激活。RNAseq 在 BCR-ABL1 和 WT 前 B 细胞中揭示了不同的 SHP2 依赖性转录程序。我们的结果表明，SHP2 通过 SFKs 和 ERK 抑制 MXD3/4 以促进 BCR-ABL1 转化的前 B 细胞中的 MYC 依赖性增殖程序。
