美国科学家近日发现一种控制干细胞快速产生和分化的基因,这一发现有望导致对于白血病和其它血癌的新型疗法。相关论文4月7日发表在《癌细胞》(Cancer Cell)上。
这一基因名为JunB,它位于调控造血干细胞(HSCs)增殖和分化的分子与环境信号复杂网络的中央。研究人员分别在培养皿和小鼠体内研究了缺乏JunB的HSCs的行为,结果发现,小鼠体内移植入HSCs后,会出现骨髓系的扩充,形成一种成熟白细胞对抗感染。移植后6到12个月,这种扩充会导致骨髓增生性疾病,有可能发展成白血病。这一发现表明,增生的缺乏JunB的HSCs会导致白血病。
就如红绿灯限速并导引车辆一样,JunB缩减HSCs的增殖及分化速度。缺失JunB,HSCs就失去了对来自蛋白受体Notch和TGF-beta的信号作出反应的能力,这两种蛋白受体位于细胞表面,对决定细胞命运具有关键性作用。
论文通讯作者、美国加州大学旧金山分校医学系的Emmanuelle Passegué说:“通过揭示这一机制,某一天我们也许能够在基因调控网络中确定正常HSCs与白血病干细胞的区别。这将使我们能够开发更多的标靶疗法。虽然目前这些治疗性应用尚未产生,但它们在血液/白血病领域能很快实现。”(生物谷Bioon.com)
生物谷推荐原始出处:
Cancer Cell,doi:10.1016/j.ccr.2009.02.016,Marianne Santaguida,Emmanuelle Passegué
JunB Protects against Myeloid Malignancies by Limiting Hematopoietic Stem Cell Proliferation and Differentiation without Affecting Self-Renewal
Marianne Santaguida1,Koen Schepers1,Bryan King1,Amit J. Sabnis2,E. Camilla Forsberg3,Joanne L. Attema4,Benjamin S. Braun2andEmmanuelle Passegué1,,
1 The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
2 Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
3 Institute for Biology of Stem Cells, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
4 Institute for Experimental Medical Science, Lund University, 221 84 Lund, Sweden
Summary
Loss of the JunB/AP-1 transcription factor induces a myeloproliferative disease (MPD) arising from the hematopoietic stem cell (HSC) compartment. Here, we show that junB inactivation deregulates the cell-cycle machinery and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without impairing their self-renewal or regenerative potential invivo. We found that JunB loss destabilizes a complex network of genes and pathways that normally limit myeloid differentiation, leading to impaired responsiveness to both Notch and TGF- signaling due in part to transcriptional deregulation of the Hes1 gene. These results demonstrate that LT-HSC proliferation and differentiation are uncoupled from self-renewal and establish some of the mechanisms by which JunB normally limits the production of myeloid progenitors, hence preventing initiation of myeloid malignancies.