8月30日出版的《基因和发育》杂志上发表的一篇报道说，造血微环境中的细胞因子影响白血病细胞增殖和对靶向治疗的耐药。
美国田纳西州圣.犹大儿童研究医院的Charles J. Sherr博士说：“对靶向治疗耐药并不是单纯因为白血病细胞本身遗传学改变，耐药是癌症细胞和宿主微环境之间复杂相互作用的净结果。”Sherr博士及其同事研究了Arf肿瘤抑制剂对于BCR－ABL诱发的白血病起始细胞（LICs）的灭活作用，并探究了白血病细胞对于靶向治疗的耐药机理。在表达人类p185 BCR－ABL异构体的小鼠干细胞中，Arf的灭活会使p185阳性白血病起始细胞增加4个对数级，而类似的表达Arf的干细胞不会诱发白血病。实际上每个p185阳性Arf阴性的供者细胞都有白血病性质，因此研究者总结说，这些白血病起始细胞不是低频的“肿瘤干细胞”。
Sherr博士说：“许多常见的人类癌症都发现了肿瘤干细胞，即这些肿瘤中，存在一些比例很低的原始细胞，这些细胞能够维持和促进肿瘤生长。进而，人们认为治疗策略的成功与否，直接与药物根治这些低频的肿瘤干细胞的能力有关。我们的研究表明，这些概念并不是放之四海而皆准的。”
他说：“我们使用了一种ph+ALL小鼠模型，这种模型中，实际上所有表达BCR－ABL激酶、缺乏Arf肿瘤抑制剂活性的细胞都能够引发和促进一种致死性耐药的白血病。研究中，分化很好的前B细胞获得无限自我更新的能力，但是不会进一步分化。” 将这些白血病起始细胞接种给动物后，长肿瘤的动物对imatinib高度耐药，但是从这些动物体内得到的白血病细胞却和供者细胞一样，对imatinib诱导的增殖抑制敏感，提示imatinib耐药可能是造血微环境引起。
Sherr博士说：“对于癌症发生发展和治疗耐药的遗传学和细胞生物学基础的认识过程，需要一个发展的、不断完善的、系统性交互的临床相关模型系统，这些模型可以用来找到直接与疾病进展相关的蛋白，提供干预这些蛋白功能的新靶向药物。”（中国公众科技网）
原始出处：
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 sherr@stjude.org ; 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).
