Thirman M J, Gill H J, Burnett R C, Mbangkollo D, McCabe N R, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, Sandberg A A
Department of Medicine, University of Chicago.
N Engl J Med. 1993 Sep 23;329(13):909-14. doi: 10.1056/NEJM199309233291302.
Translocations involving chromosome band 11q23 are very frequent in both acute lymphoblastic and acute myeloid leukemias and are the most common genetic alteration in infants with leukemia. In all age groups and all phenotypes of leukemia, an 11q23 translocation carries a poor prognosis. A major question has been whether one or several genes on band 11q23 are implicated in these leukemias. Previously, we identified the chromosomal breakpoint region in leukemias with the common 11q23 translocations and subsequently cloned a gene named MLL that spans the 11q23 breakpoint.
We isolated a 0.74-kb BamHI fragment from a complementary DAN (cDNA) clone of the MLL gene. To determine the incidence of MLL rearrangements in patients with 11q23 abnormalities, we analyzed DNA from 61 patients with acute leukemia, 3 cell lines derived from such patients, and 20 patients with non-Hodgkin's lymphoma and 11q23 aberrations.
The 0.74-kb cDNA probe detected DNA rearrangements in the MLL gene in 58 of the patients with leukemia, in the 3 cell lines, and in 3 of the patients with lymphoma. All the breaks occurred in an 8.3-kb breakpoint cluster region within the MLL gene. The probe identified DNA rearrangements in all 48 patients with the five common 11q23 translocations involving chromosomes 4, 6, 9, and 19, as well as in 16 patients with uncommon 11q23 aberrations. Twenty-one different chromosomal breakpoints involving the MLL gene were detected.
MLL gene rearrangements were detected with a single probe and a single restriction-enzyme digest in all DNA samples from patients with the common 11q23 translocations as well as in 16 patients or cell lines with other 11q23 anomalies. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation.
涉及染色体11q23带的易位在急性淋巴细胞白血病和急性髓细胞白血病中都非常常见，并且是白血病患儿中最常见的基因改变。在所有年龄组和所有白血病表型中，11q23易位都预示着预后不良。一个主要问题是11q23带上的一个还是几个基因与这些白血病有关。此前，我们确定了具有常见11q23易位的白血病中的染色体断点区域，并随后克隆了一个名为MLL的基因，该基因跨越11q23断点。
我们从MLL基因的互补DNA（cDNA）克隆中分离出一个0.74 kb的BamHI片段。为了确定11q23异常患者中MLL重排的发生率，我们分析了61例急性白血病患者、3例源自此类患者的细胞系、20例非霍奇金淋巴瘤且有11q23畸变患者的DNA。
0.74 kb的cDNA探针在58例白血病患者、3个细胞系以及3例淋巴瘤患者中检测到MLL基因中的DNA重排。所有断点都发生在MLL基因内一个8.3 kb的断点簇区域。该探针在所有48例涉及4号、6号、9号和19号染色体的五种常见11q23易位患者以及16例有罕见11q23畸变的患者中鉴定出DNA重排。检测到21个涉及MLL基因的不同染色体断点。
在所有具有常见11q23易位患者的DNA样本以及16例有其他11q23异常的患者或细胞系中，用单一探针和单一限制性内切酶消化检测到了MLL基因重排。快速可靠地检测MLL基因重排的能力，尤其是在细胞遗传学分析材料有限的患者中，应该能够识别出预后不良因此需要积极化疗或骨髓移植的患者。
