与唐氏综合征相关的急性淋巴细胞白血病中JAK2的突变
Dani Bercovich1, Ithamar Ganmore, Linda M Scott
1Human Molecular Genetics and Pharmacogenetics Laboratory, Migal-Galilee Biotechnology Centre, Kiryat Shmona, and Tel-Hai Academic College, Israel.
Lancet (London, England)
|September 23, 2008
概括
在18%的唐氏综合征和急性淋巴细胞白血病儿童中发现了JAK2 (Janus kinase 2) 的体质突变. 这些R683 JAK2突变定义了一个独特的白血病亚组,建议JAK2抑制剂作为潜在的治疗方法.
科学领域:
- 在瘤学瘤学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 患有唐氏综合征 (DS) 的儿童患急性白血病的风险明显更高,特别是急性巨核细胞白血病 (AMKL) 和急性淋巴细胞白血病 (ALL).
- 在DS中AMKL通常与GATA1突变有关,而JAK/STAT通路与其他血液癌症有关.
- 这项研究研究了JAK2突变在DS相关ALL中的作用.
研究的目的:
- 确定JAK2突变是否是与唐氏综合征 (DS) 相关的急性淋巴细胞白血病 (ALL) 的常见分子事件.
- 描述已识别的JAK2突变的功能后果.
- 探索DS-ALL的潜在治疗点.
主要方法:
- 对88名DS-ALL患者和216名患有其他白血病或精髓血小细胞衰竭的患者的骨髓样本进行了JAK2DNA突变分析.
- 鉴定突变的功能影响在小鼠的造血原生细胞和BaF3细胞中进行了评估.
- 进行了JAK2伪激酶域建模.
主要成果:
- 在16%的DS-ALL患者中检测到体内JAK2突变,所有突变都影响着保存的R683残留物.
- 患有JAK2突变的患者在诊断时显著年轻.
- 这些突变导致了造血原生细胞的不朽化,构成性的Jak/Stat激活和细胞因子独立的生长,这些细胞因应了JAK抑制剂I.
结论:
- 身体获得的R683 JAK2突变代表了独特的ALL亚型,与三症21 (唐氏综合征) 独特相关.
- 在JAK2伪激酶域突变和淋巴状或骨髓状瘤之间存在基因型-表型相关性.
- 用抑制剂向JAK2可能为这种特定的白血病亚组提供了一个有希望的治疗策略.
相关概念视频
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:15Differentiation of Common Myeloid Progenitor Cells
Common myeloid progenitors (CMPs) are oligopotent cells that can differentiate into granulocytes and macrophages. Granulocytes and macrophages are essential for protecting the body against bacterial, viral, or fungal infections. They migrate from the bone marrow into the circulating blood to reach specific tissue sites where they differentiate and help in immune surveillance. However, they survive only for a few days and must be continuously made available to the organism to maintain a robust...
01:20The Retinoblastoma Gene
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:20The Retinoblastoma Gene
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:03Rous Sarcoma Virus (RSV) and Cancer
Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...
01:03Rous Sarcoma Virus (RSV) and Cancer
Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...