Jamalpour Maria, Li Xiujuan, Gustafsson Karin, Tyner Jeffrey W, Welsh Michael
1 Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
2 Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Tumour Biol. 2018 Apr;40(4):1010428318771472. doi: 10.1177/1010428318771472.
The Src homology-2 domain protein B is an adaptor protein operating downstream of tyrosine kinases. The Shb gene knockout has been found to accelerate p210 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced leukemia. In human myeloid leukemia were tumors with high Src homology-2 domain protein B mRNA content, tumors were, however, associated with decreased latency and myeloid leukemia exhibiting immune cell characteristics. Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I-induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma. Wild-type or Shb knockout bone marrow cells expressing the oncogenes were transplanted to bone marrow-deficient recipients. Organs from moribund mice were collected and further analyzed. Shb knockout increased the development of CSF3R-induced leukemia and increased the white blood cell count at the time of death. In the p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase B-cell model, Shb knockout reduced white blood cell counts without affecting latency, whereas in the G12D-Kras T-cell model, thymus size was increased without major effects on latency, suggesting that Shb knockout accelerates the development thymic lymphoma. Cytokine secretion plays a role in the progression of leukemia, and consequently Shb knockout bone marrows exhibited lower expression of granulocyte colony stimulating factor and interleukin 6 in the neutrophilic model and interleukin 7 and chemokine C-X-C motif ligand 12 (C-X-C motif chemokine 12) in the B-cell model. It is concluded that in experimental mouse models, the absence of the Shb gene exacerbates the disease in myeloid leukemia, whereas it alters the disease characteristics without affecting latency in B- and T-cell leukemia. The results suggest a role of Shb in modulating the disease characteristics depending on the oncogenic insult operating on hematopoietic cells. These findings help explain the outcome of human disease in relation to Src homology-2 domain protein B mRNA content.
Src同源2结构域蛋白B是一种在酪氨酸激酶下游起作用的衔接蛋白。已发现Shb基因敲除会加速p210断裂簇区域 - cAbl原癌基因1酪氨酸激酶诱导的白血病。在人类髓系白血病中，肿瘤具有高Src同源2结构域蛋白B mRNA含量，但肿瘤与潜伏期缩短相关，且髓系白血病表现出免疫细胞特征。因此，本研究的目的是在另外三种模型中研究Shb基因敲除对白血病发展的影响，即集落刺激因子3受体 - T618I诱导的嗜中性粒细胞白血病、p190断裂簇区域 - cAbl原癌基因1酪氨酸激酶诱导的B细胞白血病以及G12D - Kras诱导的T细胞白血病/胸腺淋巴瘤。将表达癌基因的野生型或Shb基因敲除的骨髓细胞移植到骨髓缺陷受体中。收集濒死小鼠的器官并进行进一步分析。Shb基因敲除增加了CSF3R诱导的白血病的发展，并增加了死亡时的白细胞计数。在p190断裂簇区域 - cAbl原癌基因1酪氨酸激酶B细胞模型中，Shb基因敲除降低了白细胞计数，但不影响潜伏期，而在G12D - Kras T细胞模型中，胸腺大小增加，对潜伏期没有重大影响，这表明Shb基因敲除加速了胸腺淋巴瘤的发展。细胞因子分泌在白血病进展中起作用，因此在嗜中性粒细胞模型中，Shb基因敲除的骨髓中粒细胞集落刺激因子和白细胞介素6的表达较低，在B细胞模型中白细胞介素7和趋化因子C - X - C基序配体12（C - X - C基序趋化因子12）的表达较低。得出的结论是，在实验小鼠模型中，Shb基因的缺失会加重髓系白血病的病情，而在B细胞和T细胞白血病中，它会改变疾病特征但不影响潜伏期。结果表明，Shb在根据作用于造血细胞的致癌损伤调节疾病特征方面发挥作用。这些发现有助于解释与Src同源2结构域蛋白B mRNA含量相关的人类疾病的结果。
