Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

被引:61
作者
Cuenco, GM [1 ]
Ren, RB [1 ]
机构
[1] Brandeis Univ, Dept Biol, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA
关键词
BCR; -; ABL; AML1/MDS1/EVI1; AML; differentiation;
D O I
10.1038/sj.onc.1205095
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice. but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BRC-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.
引用
收藏
页码:8236 / 8248
页数:13
相关论文
共 42 条
  • [11] Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
    Gorre, ME
    Mohammed, M
    Ellwood, K
    Hsu, N
    Paquette, R
    Rao, PN
    Sawyers, CL
    [J]. SCIENCE, 2001, 293 (5531) : 876 - 880
  • [12] Gross AW, 1999, MOL CELL BIOL, V19, P6918
  • [13] Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder
    Hao, SX
    Ren, RB
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (04) : 1149 - 1161
  • [14] HEUTTNE CS, 2000, NAT GENET, V24, P57
  • [15] Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia
    Horiike, S
    Yokota, S
    Nakao, M
    Iwai, T
    Sasai, Y
    Kaneko, H
    Taniwaki, M
    Kashima, K
    Fujii, H
    Abe, T
    Misawa, S
    [J]. LEUKEMIA, 1997, 11 (09) : 1442 - 1446
  • [16] JACOBS A, 1991, LEUKEMIA, V5, P277
  • [17] Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product
    Kiyoi, H
    Towatari, M
    Yokota, S
    Hamaguchi, M
    Ohno, R
    Saito, H
    Naoe, T
    [J]. LEUKEMIA, 1998, 12 (09) : 1333 - 1337
  • [18] LOSS OF ERYTHROPOIETIN RESPONSIVENESS IN ERYTHROID PROGENITORS DUE TO EXPRESSION OF THE EVI-1 MYELOID-TRANSFORMING GENE
    KREIDER, BL
    ORKIN, SH
    IHLE, JN
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (14) : 6454 - 6458
  • [19] The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity
    Li, SG
    Ilaria, RL
    Million, RP
    Daley, GQ
    Van Etten, RA
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (09) : 1399 - 1412
  • [20] Erythroid defects and increased retrovirally-induced tumor formation in Evi1 transgenic mice
    Louz, D
    van den Broek, M
    Verbakel, S
    Vankan, Y
    van Lom, K
    Joosten, M
    Meijer, D
    Löwenberg, B
    Delwel, R
    [J]. LEUKEMIA, 2000, 14 (11) : 1876 - 1884