急性淋巴细胞白血病(Acute Lymphoblastic Leukemia，简称ALL)是一种癌症，患者的白血球不正常的增生，超过身体所需要的量。圣犹大儿童医院(St. Jude Children's Research Hospital)的研究人员发现ALL的成因是由基因突变所致，这项研究发现不仅提供了ALL的新治疗方法的线索，也对成人血癌的成因提供了另一张研究指引的地图。
研究人员利用微芯片(microarrays)分析，芯片中大约包含35万种单点核酸变异(Single Nucleotide Polymorphisms，简称SNP)的指标，以便进行人类染色体变异的侦测，分析了242位有ALL的儿童病患，意外的找到了一系列突变的基因，这些基因主要负责调控B细胞的发育及分化。此研究发表于3月7日的Nature期刊。
研究中发现40%的ALL病人在”master genes”上有缺失(deletions)或突变(mutations)的现象，master genes主要负责B细胞的分化；而30%的病人其”PAX5”基因已突变，使得PAX5的表现量下降，无法在白血球细胞中发挥其正常功能；此外，会影响B细胞发育及分化的基因，如：EBF1以及Ikaros也都有突变的情况。研究人员表示PAX5, EBF及Ikaros等基因都是转译因子(transcription factors)，会影响许多造成B细胞发育的蛋白质，当B细胞无法正常的发育，未成熟的细胞又不断的增生，在很短的时间内便会导致患病的儿童死亡。
病理学院院长James Downing医师表示：「利用微芯片的方法筛选染色体的变异，不仅能找出ALL的基因缺陷，也能找出其它癌症的成因。」美国癌症协会(American Cancer Society)的Ching-Hon Pui教授则说：「这项研究相当具有价值，让我们清楚的知道为何白血球会停留在未成熟的阶段，形成癌化的现象，也提供一条治疗ALL的好线索。」
Downing博士说：「如果我们设计的药物能绕过这个B细胞分化的路障，就可以将那些无法成熟的白血球变为成熟且具功能性的白血球，那么成熟的B细胞就能辨识出那些有缺陷的白血球，进而消灭他们。」
(资料来源 : 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.
