Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model.
Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model.
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DOI：
10.18632/oncotarget.10210
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发表时间：
2016-08-09
期刊：
影响因子：
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通讯作者：
Hamaguchi I
中科院分区：
文献类型：
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作者：
Kuribayashi W;Takizawa K;Sugata K;Kuramitsu M;Momose H;Sasaki E;Hiradate Y;Furuhata K;Asada Y;Iwama A;Matsuoka M;Mizukami T;Hamaguchi I
成人T细胞白血病（ATL）是由人类嗜T淋巴细胞病毒1型引起的恶性疾病。在侵袭性ATL中，对化疗的反应极差。我们假设这种不良反应是由于化疗耐药细胞的存在，如白血病干细胞。之前，我们使用Tax转基因小鼠在ATL小鼠模型中成功鉴定了ATL干细胞（ATLSC）候选者作为c-kit+/CD 38 −/CD 71 −细胞。在这里，通过使用HBZ转基因小鼠的新ATL小鼠模型，我们进一步发现通常表达c-kit的功能性ATL SC候选物具有耐药性，并且具有引发肿瘤和重建淋巴瘤细胞的能力。我们将ATLSC表征为c-kit+/CD 4 −/CD 8 −细胞，并发现它们具有与T细胞祖细胞相似的基因表达谱。此外，我们发现AP-1基因家族成员，包括Junb，Jund和Fosb，在ATL SC组分中上调。体外测定的结果显示，用已知促进干细胞扩增的细胞因子（例如干细胞因子（SCF））培养的ATLSC显示出高度增殖活性并维持其干细胞分数。用中和抗体ACK 2抑制c-kit-SCF信号传导影响ATL SC的自我更新和增殖。在膜结合c-kit配体中具有突变的Sl/Sld小鼠中的实验发现，ATL发育在这些小鼠中被完全阻断。这些结果清楚地表明，c-kit-SCF信号在ATL SC自我更新和ATL启动和疾病进展中起关键作用。
Adult T-cell leukemia (ATL) is a malignant disease caused by human T-lymphotropic virus type 1. In aggressive ATL, the response to chemotherapy is extremely poor. We hypothesized that this poor response is due to the existence of chemotherapy-resistant cells, such as leukemic stem cells. Previously, we successfully identified an ATL stem cell (ATLSC) candidate as the c-kit+/CD38−/CD71− cells in an ATL mouse model using Tax transgenic mice. Here, with a new ATL mouse model using HBZ-transgenic mice, we further discovered that the functional ATLSC candidate, which commonly expresses c-kit, is drug-resistant and has the ability to initiate tumors and reconstitute lymphomatous cells. We characterized the ATLSCs as c-kit+/CD4−/CD8− cells and found that they have a similar gene expression profile as T cell progenitors. Additionally, we found that AP-1 gene family members, including Junb, Jund, and Fosb, were up-regulated in the ATLSC fraction. The results of an in vitro assay showed that ATLSCs cultured with cytokines known to promote stem cell expansion, such as stem cell factor (SCF), showed highly proliferative activity and maintained their stem cell fraction. Inhibition of c-kit–SCF signaling with the neutralizing antibody ACK2 affected ATLSC self-renewal and proliferation. Experiments in Sl/Sld mice, which have a mutation in the membrane-bound c-kit ligand, found that ATL development was completely blocked in these mice. These results clearly suggest that the c-kit–SCF signal plays a key role in ATLSC self-renewal and in ATL initiation and disease progression.