ダウン症候群に関連した急性リンパ性白血病におけるJAK2の変異
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
まとめ
JAK2 (Janus kinase 2) の体内の変異は,ダウン症候群と急性リンパ性白血病の子供の18%で発見されました. これらのR683 JAK2変異は,ユニークな白血病サブグループを定義し,JAK2阻害剤を潜在的な治療法として示唆しています.
科学分野:
- 腫瘍学 腫瘍学
- 遺伝学 遺伝学とは
- 分子生物学は分子生物学である.
背景:
- ダウン症候群 (DS) の子供は,急性白血病,特に急性メガカリオブラスティック白血病 (AMKL) と急性リンパ性白血病 (ALL) のリスクが著しく高い.
- DSにおけるAMKLはしばしばGATA1変異と関連しており,JAK/STAT経路は他の血液がんに関与している.
- この研究では,DSに関連したALLにおけるJAK2変異の役割を調査しました.
研究 の 目的:
- JAK2変異がダウン症候群 (DS) と関連した急性リンパ性白血病 (ALL) の一般的な分子イベントであるかどうかを判断する.
- 特定されたJAK2変異の機能的影響を特徴付けるため.
- DS-ALLの潜在的な治療目標を探求する.
主な方法:
- JAK2DNA変異分析は,DS-ALLの88人の患者と,他の白血病または精性血栓塞血症の216人の患者からの骨髄サンプルで行われました.
- 特定された突然変異の機能的効果は,マウスの血液形成原始細胞とBaF3細胞で評価されました.
- JAK2 pseudokinase ドメインモデリングが行われました.
主要な成果:
- ソマティックJAK2変異は,DS-ALL患者の16%で検出され,すべての変異は保存されたR683残基に影響しました.
- JAK2変異を有する患者は,診断時に著しく若かった.
- これらの突然変異は,血液形成の原始細胞の不死化,構成的なJak/Statの活性化,およびJAK阻害剤Iに反応したサイトカイン依存の成長につながった.
結論:
- 身体的に獲得されたR683 JAK2変異は,トリソミー21 (ダウン症候群) とユニークな関連性を持つALLの独特のサブタイプを表しています.
- JAK2偽キナーゼドメイン変異とリンパ性または骨髄性腫瘍の間に遺伝子型-現象型相関が存在します.
- JAK2を阻害剤で標的化することは,この特定の白血病サブグループにとって有望な治療戦略を提供することができる.
関連する概念動画
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...