期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 17, 页码 6688-6693出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602030103
关键词
Arf tumor suppressor; Gleevec; IL-7; JAK kinases; drug resistance
资金
- NCI NIH HHS [T32 CA070089, P30 CA021765, CA-21765, T32-CA70089, CA-71907, P01 CA071907] Funding Source: Medline
Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210(Bcr-Abl) and p(185Bcr-Abl)) induce B cell lympholeukemias when transplanted into lethally irradiated mice. If the activity of the Arf tumor suppressor is compromised, these donor cells initiate a much more highly aggressive and rapidly fatal disease. When mouse bone marrow cells expressing Bcr-Abl are placed in short-term cultures selectively designed to support the outgrowth of pre-B cells, only those lacking one or two Arf alleles can initiate lympholeukemias when inoculated into immunocompetent, syngeneic recipient mice. Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF (CDKN2A) tumor suppressor locus. Mice receiving Arf(-/-) or Arf(+/-) p210(Bcr-Abl)-positive pre-B cells do not achieve remission when maintained on high doses of oral imatinib therapy and rapidly succumb to lympholeukemia. Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib. Treatment of Arf(-/-), p210(Bcr-Abl)-positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据