急性淋巴細(xì)胞白血病(Acute Lymphoblastic Leukemia,，簡(jiǎn)稱(chēng)ALL)是一種癌癥，患者的白血球不正常的增生,，超過(guò)身體所需要的量,。圣猶大兒童醫(yī)院(St. Jude Children's Research Hospital)的研究人員發(fā)現(xiàn)ALL的成因是由基因突變所致，這項(xiàng)研究發(fā)現(xiàn)不僅提供了ALL的新治療方法的線(xiàn)索,，也對(duì)成人血癌的成因提供了另一張研究指引的地圖,。
研究人員利用微芯片(microarrays)分析，芯片中大約包含35萬(wàn)種單點(diǎn)核酸變異(Single Nucleotide Polymorphisms,，簡(jiǎn)稱(chēng)SNP)的指標(biāo),，以便進(jìn)行人類(lèi)染色體變異的偵測(cè),，分析了242位有ALL的兒童病患，意外的找到了一系列突變的基因,，這些基因主要負(fù)責(zé)調(diào)控B細(xì)胞的發(fā)育及分化,。此研究發(fā)表于3月7日的Nature期刊。
研究中發(fā)現(xiàn)40%的ALL病人在”master genes”上有缺失(deletions)或突變(mutations)的現(xiàn)象,，master genes主要負(fù)責(zé)B細(xì)胞的分化,；而30%的病人其”PAX5”基因已突變,，使得PAX5的表現(xiàn)量下降,，無(wú)法在白血球細(xì)胞中發(fā)揮其正常功能；此外,，會(huì)影響B(tài)細(xì)胞發(fā)育及分化的基因,，如：EBF1以及Ikaros也都有突變的情況。研究人員表示PAX5, EBF及Ikaros等基因都是轉(zhuǎn)譯因子(transcription factors),，會(huì)影響許多造成B細(xì)胞發(fā)育的蛋白質(zhì),，當(dāng)B細(xì)胞無(wú)法正常的發(fā)育，未成熟的細(xì)胞又不斷的增生，在很短的時(shí)間內(nèi)便會(huì)導(dǎo)致患病的兒童死亡,。
病理學(xué)院院長(zhǎng)James Downing醫(yī)師表示：「利用微芯片的方法篩選染色體的變異,，不僅能找出ALL的基因缺陷，也能找出其它癌癥的成因,?！姑绹?guó)癌癥協(xié)會(huì)(American Cancer Society)的Ching-Hon Pui教授則說(shuō)：「這項(xiàng)研究相當(dāng)具有價(jià)值，讓我們清楚的知道為何白血球會(huì)停留在未成熟的階段,，形成癌化的現(xiàn)象,，也提供一條治療ALL的好線(xiàn)索?！?
Downing博士說(shuō)：「如果我們?cè)O(shè)計(jì)的藥物能繞過(guò)這個(gè)B細(xì)胞分化的路障,，就可以將那些無(wú)法成熟的白血球變?yōu)槌墒烨揖吖δ苄缘陌籽?，那么成熟的B細(xì)胞就能辨識(shí)出那些有缺陷的白血球，進(jìn)而消滅他們,?！?/p>
(資料來(lái)源 : Bio.com)
Major gene study uncovers secrets of leukemia
St. Jude study scans 350,000 locations across the genome from 242 patients and identifies new mutations that contribute to acute lymphoblastic leukemia, suggesting new targets for improved therapy
Investigators at St. Jude Children's Research Hospital have discovered previously unsuspected mutations that contribute to the formation of pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children. The discovery not only suggests novel methods for treating pediatric ALL, but also provides a roadmap for the identification of unsuspected mutations in adult cancers.
ALL is a tumor in which immature white blood cells that normally develop into immune system cells, called B or T lymphocytes, instead multiply rapidly and overwhelm the normal blood cells the body needs to survive.
The St. Jude team used microarrays, postage-stamp-sized chips that contain DNA fragments, which allowed researchers to investigate more than 350,000 markers called single nucleotide polymorphisms. Single nucleotide polymorphisms are individual variations in the DNA that are spaced across the human chromosomes. Single nucleotide polymorphisms function as flags for researchers, allowing them to detect specific deletions of DNA in a gene or increases in the number of specific genes at a level of detail that was previously unattainable. The St. Jude group used this approach to analyze leukemia samples from 242 pediatric patients with ALL. This identified an unexpectedly high frequency of mutations involving genes that function as master regulators of normal B-cell development and differentiation.
A report on this work appears in the March 7 online edition of "Nature."
"The results of our study demonstrate that it is possible to significantly speed the identification of the genetic lesions that are the underlying cause of not only ALL, but also many other cancers, including those affecting adults," said James Downing, M.D., scientific director and chair of the Pathology department at St. Jude. He is senior author of the paper.
The study found that 40 percent of patients with ALL had deletions or mutations in one of three so-called "master genes" that control the normal differentiation of immature progenitor cells into mature B lymphocytes.
The researchers found that the "PAX5" gene was most frequently mutated梐ltered in about 30 percent of patients. These mutations reduced the level of PAX5 protein in leukemic cells or resulted in the formation of PAX5 protein with defective function. Mutations were also found in other genes with important roles in B-cell differentiation including "EBF1" and "Ikaros."
"Although the identification of such a high frequency of mutations in this pathway was surprising, it is important to note that the approach used provides a lower limit of the true frequency of these mutations, since not every gene in this pathway could be accurately analyzed using this methodology," Downing said.
The mutations identified in "PAX5," "EBF" and "Ikaros" are likely to directly contribute to this block in normal lymphocyte differentiation, according to Downing. These genes encode proteins called transcription factors, which orchestrate the expression of a large number of other genes involved in B cell development. Together these genes coordinate the complex changes needed to induce progenitor cells to differentiate into B lymphocytes. In ALL, the leukemic cells fail to differentiate normally and instead remain blocked at an immature stage of development. Locked in this state, the leukemic cells continue to proliferate, and this continual growth of leukemic cells eventually kills the child.
"The new insights into the differentiation of B cells are extremely valuable," said Ching-Hon Pui, M.D., chair of the Oncology department and American Cancer Society Professor at St. Jude. Pui co-authored the paper. "The more we learn about why progenitor cells get stuck in the primitive, cancerous stage, the more likely we'll be able to design new therapies that eliminate them. That could help us continue our successful efforts to increase the survival rate of ALL."
One potential strategy for eliminating leukemic cells would take advantage of the discovery that mutations in the B-cell differentiation pathway are predicted to prevent progenitors from changing into normally functioning lymphocytes. Normally, the body eliminates differentiated B lymphocytes that have failed to assemble the right genes to make effective antibodies against the specific target they are supposed to attack. However, if these defective B lymphocytes do not differentiate because of the mutations, the body will not recognize them as defective immune cells and destroy them. Instead, these undifferentiated cells continue to multiply, causing ALL.
"If we could design a drug that bypasses the roadblock to differentiation, we could push these cells to become fully mature B lymphocytes," Downing said. "And then the body would recognize them as defective B lymphocytes and destroy them."
The other authors of this paper include William E. Evans, Mary V. Relling, Charles G. Mullighan, Salil Goorha, Ina Radtke, Christopher B. Miller, Elaine Coustan-Smith, James D. Dalton, Kevin Girtman, Susan Mathew, Jing Ma, Stanley B. Pounds, Xiaoping Su and Sheila A. Shurtleff.
This work was supported in part by the National Cancer Institute, the National Institute of General Medical Sciences, the National Health and Medical Research Council (Australia), the Royal Australasian College of Physicians, the Haematology Society of Australia and New Zealand, and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
