JAK2V617F-dependent down regulation of SHP-1 expression participates in the selection of myeloproliferative neoplasm cells in the presence of TGF-β

IF 5.3
Céline Aoun, Nabih Maslah, Saravanan Ganesan, Norman Salomao, Romane Gendron, Sarah Awan Toor, Gil Letort, Panhong Gou, Mélina Bonnamy, Véronique Parietti, Jean-Jacques Kiladjian, Stephane Giraudier, Bruno Cassinat
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Abstract

Myeloproliferative neoplasms (MPNs) are characterized by an increased production of blood cells due to the acquisition of mutations such as JAK2V617F. TGF-β, whose secretion is increased in MPN patients, is known to negatively regulate haematopoietic stem cell (HSC) proliferation. Using an isogenic JAK2V617F or JAK2 wild-type UT-7 cell line we observed that JAK2V617F cells resist to TGF-β antiproliferative activity. Although TGF-β receptors and SMAD2/3 expressions are similar in both cell types, TGF-β-induced phosphorylation of SMAD2/3 is reduced in UT-7 JAK2V617F cells compared with JAK2 WT cells. We confirmed that JAK2V617F mutated cells are resistant to the antiproliferative effect of TGF-β in a competitive assay as we observed a positive selection of JAK2V617F cells when exposed to TGF-β. Using cell lines, CD34-positive cells from MPN patients and bone marrow cells from JAK2V617F knock-in mice we identified a down regulation of the SHP-1 phosphatase, which is required for the regulation of HSC quiescence by TGF-β. The transduction of SHP-1 cDNA (but not a phosphatase inactive cDNA) restores the antiproliferative effect of TGF-β in JAK2V617F mutated cells. Finally, SC-1, a known agonist of SHP-1, antagonized the selection of JAK2V617F mutated cells in the presence of TGF-β. In conclusion, we show a JAK2-dependent down regulation of SHP-1 in MPN patients' cells which is related to their resistance to the antiproliferative effect of TGF-β. This may participate in the clonal selection of cancer cells in MPNs.

Abstract Image

依赖于 JAK2V617F 的 SHP-1 表达下调参与了骨髓增生性肿瘤细胞在 TGF-β 存在下的选择。
骨髓增殖性肿瘤(MPNs)的特点是由于发生了 JAK2V617F 等突变而导致血细胞生成增加。TGF-β 在骨髓增殖性肿瘤患者中分泌增加,众所周知,它能对造血干细胞(HSC)的增殖产生负面调节作用。通过使用同源的JAK2V617F或JAK2野生型UT-7细胞系,我们观察到JAK2V617F细胞对TGF-β抗增殖活性有抵抗力。虽然TGF-β受体和SMAD2/3在两种细胞类型中的表达相似,但与JAK2 WT细胞相比,TGF-β诱导的SMAD2/3磷酸化在UT-7 JAK2V617F细胞中有所降低。我们在竞争性试验中证实,JAK2V617F 突变细胞对 TGF-β 的抗增殖作用有抵抗力,因为我们观察到 JAK2V617F 细胞在暴露于 TGF-β 时会出现阳性选择。通过使用细胞系、来自骨髓增生性疾病患者的 CD34 阳性细胞以及 JAK2V617F 基因敲入小鼠的骨髓细胞,我们发现了 TGF-β 对造血干细胞静止调节所需的 SHP-1 磷酸酶的下调作用。转导SHP-1 cDNA(而非无磷酸酶活性的cDNA)可恢复TGF-β对JAK2V617F突变细胞的抗增殖作用。最后,SHP-1 的已知激动剂 SC-1 在 TGF-β 的存在下拮抗了 JAK2V617F 突变细胞的选择。总之,我们发现 MPN 患者细胞中的 SHP-1 受 JAK2 依赖性下调,这与它们对 TGF-β 抗增殖作用的抵抗有关。这可能参与了 MPN 中癌细胞的克隆选择。
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CiteScore
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期刊介绍: The Journal of Cellular and Molecular Medicine serves as a bridge between physiology and cellular medicine, as well as molecular biology and molecular therapeutics. With a 20-year history, the journal adopts an interdisciplinary approach to showcase innovative discoveries. It publishes research aimed at advancing the collective understanding of the cellular and molecular mechanisms underlying diseases. The journal emphasizes translational studies that translate this knowledge into therapeutic strategies. Being fully open access, the journal is accessible to all readers.
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