8月30日出版的《基因和發(fā)育》雜志上發(fā)表的一篇報道說,，造血微環(huán)境中的細(xì)胞因子影響白血病細(xì)胞增殖和對靶向治療的耐藥,。
美國田納西州圣.猶大兒童研究醫(yī)院的Charles J. Sherr博士說：“對靶向治療耐藥并不是單純因為白血病細(xì)胞本身遺傳學(xué)改變，耐藥是癌癥細(xì)胞和宿主微環(huán)境之間復(fù)雜相互作用的凈結(jié)果,。”Sherr博士及其同事研究了Arf腫瘤抑制劑對于BCR－ABL誘發(fā)的白血病起始細(xì)胞（LICs）的滅活作用,，并探究了白血病細(xì)胞對于靶向治療的耐藥機理。在表達(dá)人類p185 BCR－ABL異構(gòu)體的小鼠干細(xì)胞中,，Arf的滅活會使p185陽性白血病起始細(xì)胞增加4個對數(shù)級,，而類似的表達(dá)Arf的干細(xì)胞不會誘發(fā)白血病,。實際上每個p185陽性Arf陰性的供者細(xì)胞都有白血病性質(zhì),，因此研究者總結(jié)說，這些白血病起始細(xì)胞不是低頻的“腫瘤干細(xì)胞”,。
Sherr博士說：“許多常見的人類癌癥都發(fā)現(xiàn)了腫瘤干細(xì)胞,，即這些腫瘤中，存在一些比例很低的原始細(xì)胞,，這些細(xì)胞能夠維持和促進(jìn)腫瘤生長。進(jìn)而,，人們認(rèn)為治療策略的成功與否,，直接與藥物根治這些低頻的腫瘤干細(xì)胞的能力有關(guān)。我們的研究表明,，這些概念并不是放之四海而皆準(zhǔn)的,。”
他說：“我們使用了一種ph+ALL小鼠模型，這種模型中,，實際上所有表達(dá)BCR－ABL激酶,、缺乏Arf腫瘤抑制劑活性的細(xì)胞都能夠引發(fā)和促進(jìn)一種致死性耐藥的白血病。研究中,，分化很好的前B細(xì)胞獲得無限自我更新的能力,，但是不會進(jìn)一步分化,。” 將這些白血病起始細(xì)胞接種給動物后，長腫瘤的動物對imatinib高度耐藥,，但是從這些動物體內(nèi)得到的白血病細(xì)胞卻和供者細(xì)胞一樣,，對imatinib誘導(dǎo)的增殖抑制敏感，提示imatinib耐藥可能是造血微環(huán)境引起,。
Sherr博士說：“對于癌癥發(fā)生發(fā)展和治療耐藥的遺傳學(xué)和細(xì)胞生物學(xué)基礎(chǔ)的認(rèn)識過程,，需要一個發(fā)展的、不斷完善的,、系統(tǒng)性交互的臨床相關(guān)模型系統(tǒng)，這些模型可以用來找到直接與疾病進(jìn)展相關(guān)的蛋白,，提供干預(yù)這些蛋白功能的新靶向藥物,。”（中國公眾科技網(wǎng)）
原始出處：
Published online before print August 30, 2007, 10.1101/gad.1588607
GENES & DEVELOPMENT 21:2283-2287, 2007
Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia
Richard T. Williams1, Willem den Besten2,3, and Charles J. Sherr2,3,4
1 Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA; 2 Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA; 3 Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
Retroviral transduction of the BCR-ABL kinase into primary mouse bone marrow cells lacking the Arf tumor suppressor rapidly generates polyclonal populations of continuously self-renewing pre-B cells, virtually all of which have leukemic potential. Intravenous infusion of 20 such cells into healthy syngeneic mice induces rapidly fatal, transplantable lymphoblastic leukemias that resist imatinib therapy. Introduction of BCR-ABL into Arf-null severe combined immunodeficient (SCID) bone marrow progenitors lacking the cytokine receptor common -chain yields leukemogenic pre-B cells that exhibit greater sensitivity to imatinib in vivo. Hence, salutary cytokines in the hematopoietic microenvironment can facilitate leukemic proliferation and confer resistance to targeted therapy.
[Keywords: BCR-ABL kinase; Arf tumor suppressor; imatinib (Gleevec); leukemia-initiating cells; cytokines; drug resistance]
Received June 29, 2007; revised version accepted July 25, 2007.
4 Corresponding author.
E-MAIL [email protected] ; FAX (901) 495-2381.
Supplemental material is available at http://www.genesdev.org.
Figure 1. Assessment of pre-B-cell clonality. (A) DNA extracted from mouse tail (control, lane C) or from 20 clones derived at random from single cells (lanes 1–20) was digested with XbaI, electrophoretically separated on agarose gels, transferred to nylon, and hybridized with a JH probe that detects Ig heavy-chain gene rearrangements. The unrearranged germline band is visualized in lane C, whereas two bands observed in the other lanes result from rearrangements affecting the two Ig heavy-chain alleles. The panel represents a composite of data from two parallel gels. (B) The same DNAs were digested with EcoRI and probed for GFP sequences. Because EcoRI recognizes a single restriction site 5' to the GFP gene, proviruses integrated at different sites yield hybridizing fragments of variable lengths that contain different host cell sequences adjoining their 3' long-terminal repeat. Each hybridizing band corresponds to a single site of proviral insertion. Clones 9 and 15 sustained two integrations, whereas the remaining clones had one. (C) DNAs extracted from bone marrow of individual leukemic animals that had received 2000, 200, or 20 p185+, Arf-null cells (as noted at the top) were studied for viral integrations as in B. Proviruses molecularly cloned from the monoclonal leukemias illustrated in C were integrated at distinct loci on six different chromosomes (Supplementary Table S2).
