研究者发现基因突变如何导致滤泡性淋巴瘤
一种叫做kmt2d在所有滤泡性淋巴瘤肿瘤中至少有一半突变。一个令人吃惊的发现表明，该基因并没有直接驱动控制细胞的生长，而是通过一种称为表观遗传调控的过程来控制其他基因的活性。了解分子原因是一个重要的一步，对新的和更好的治疗方法，这种常见的，不可治愈的形式，非霍奇金淋巴瘤。
Highlights Follicular lymphoma has remained incurable。 一种叫做kmt2d在这种疾病中经常突变。 研究表明，这种突变导致不受控制的细胞生长。 这是一个更有效的治疗方法的重要一步。在过去的几十年中，在发展新的治疗滤泡性淋巴瘤，非霍奇金淋巴瘤的最常见形式的进展已经没有什么进展了。这种疾病，它涉及到的白血细胞的异常白细胞，通常是缓慢增长，但仍然被认为是不可治愈的。由于缺乏细胞系和良好的动物模型，它也被证明是很难研究的。
纪念斯隆-凯特琳研究人员为首的癌症生物学家汉斯Guido温德尔，与Weill康奈尔医学院的实验室Ari Melnick合作，制定了关于滤泡性淋巴瘤的分子基础，一个令人吃惊的发现。 ；本病最常见的基因突变，kmt2d，不通过典型的机制，直接作用于驱动不受控制的细胞生长，不会导致癌症。相反，它通过一个称为表观遗传调控的过程来控制其他基因的活动。
[kmt2d] is the most important mutation in this incurable disease。
汉斯Guido温德尔
癌症生物学家&ldquo；这种不可治愈的疾病最重要的突变，我们找到了它，&rdquo；温德尔博士说。 ；&ldquo；了解分子的原因是对新的和更好的治疗方法的重要一步。例如，新兴的药物能够靶向的一些 ； ；这些信号通路可能与这些肿瘤是有效的。”；
这一发现是在网上发布的自然医学。
突变的连锁反应
Epigenetics relates to a gene’s functioning being changed by factors unrelated to the sequence of its DNA。 Epigenetic changes are a normal part of many biological processes, but they also can lead to cancer and other diseases。
kmt2d operates through an epigenetic mechanism called histone modification。 Histones are proteins that DNA wraps around like yarn on a spool。 In effect, if the DNA is wrapped too tightly, it is unable to unspool and the genes encoded on it cannot be expressed — they remain “off。” If it’s too loose, genes that should remain silent may be activated。
When the kmt2d gene is mutated, other genes fail to switch on。The tightness or looseness of the DNA — and resulting gene expression — is regulated by histone modifying enzymes, or HMEs, which “mark” a histone to alter it。 The kmt2d gene produces an HME that uses this process to turn on an array of genes that manage B cell growth and prevent the cells from becoming malignant。
“We found that the kmt2d enzyme activates a large number of genes, many of which are essential to the normal production of B cells,” explains Ana Ortega-Molina, a postdoctoral research fellow in Dr。 Wendel’s laboratory and one of the first authors of the study。 “When the kmt2d gene is mutated, these other genes fail to switch on, and the B cells don’t receive the signal to stop dividing when they should。 This results in the proliferation of abnormal B cells that leads to follicular lymphoma。”
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kmt2d is one of the most frequently mutated genes across all cancer types。 This is especially true for follicular lymphoma — at least 50 percent of tumors have kmt2d gene mutations。
这些突变的频率表明，这可能是癌症的主要原因之一kmt2d an inviting target for study。 However, until recently it was difficult to design a way to clarify its normal function — and to figure out how the breakdown of that function could cause the disease。
A key step forward was the Wendel lab’s development of a follicular lymphoma mouse model in 2011。 This tool is now broadly used by scientists working on lymphoma and allows researchers to conduct experiments clarifying the function of specific genes mutated in follicular lymphoma cells and to test new therapies。
在自然医学 study, Dr。 Ortega-Molina used this model to test what happened when kmt2d activity is blocked。 She found that loss of the enzyme’s function caused the mice to develop more advanced follicular lymphoma tumors even more rapidly, demonstrating a functional link between the gene mutation and the disease。
肿瘤的遗传分析允许她和她的合作者威尔康奈尔定义如何导致癌症和基因突变有直接影响时kmt2d is mutated。
&ldquo；安娜是表明第一人kmt2d acts as a tumor suppressor through epigenetic regulation of critical growth and survival pathways in B cells,” Dr。 Wendel says。
他补充说，澄清kmt2d’s role could guide new treatment strategies。 “We know that mutation of kmt2d leads to loss of a specific mark on histone proteins,” he explains。 “We also know which other genes are responsible for removing this mark as part of their normal function。 We can speculate that inhibitors of these removal factors may restore the balance and could be effective against lymphomas caused by mutated kmt2d。”
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