The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1-CD44 axis
The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1-CD44 axis
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DOI：
10.3324/haematol.2018.212365
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发表时间：
2020-01-01
期刊：
影响因子：
10.1
通讯作者：
Krause, Daniela S.
中科院分区：
文献类型：
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作者：
Godavarthy, Parimala Sonika;Kumar, Rahul;Krause, Daniela S.
骨内膜骨髓龛和血管内皮细胞为白血病细胞提供庇护所。在小鼠慢性粒细胞白血病（CML）中，白血病细胞上的CD 44和骨髓内皮细胞上的E-选择素是白血病干细胞植入的重要介质。我们假设CML起始细胞不粘附于骨髓内皮细胞上的E-选择素可能导致伊马替尼治疗后CML中白血病干细胞的根除优于单独使用伊马替尼。事实上，在这里，我们表明，E-选择素抑制剂GMI-1271与伊马替尼联合治疗通过减少白血病细胞与骨髓内皮细胞的接触时间来提高CML小鼠的存活率。BCR-ABL 1（+）细胞的非粘附性导致白血病起始细胞中细胞周期进程的增加以及造血转录因子和原癌基因Scl/Tal 1表达的增加。我们认为SCL/TAL 1是BCR-ABL 1的间接磷酸化靶点，也是CD 44表达的负转录调节因子。我们发现SCL/TAL 1表达增加与人类CML预后改善相关。这些数据表明，BCR-ABL 1特异性的细胞内在途径通过调节粘附分子导致与血管生态位的相互作用改变-这可以在未来进行治疗。
The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1(+) cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.