TY - JOUR
T1 - Idl is a common downstream target of oncogenic tyrosine kinases in leukemic cells
AU - Tarn, Winnie F.
AU - Gu, Ting Lei
AU - Chen, Jing
AU - Lee, Benjamin H.
AU - Bullinger, Lars
AU - Frohling, Stefan
AU - Wang, Andrew
AU - Monti, Stefano
AU - Golub, Todd R.
AU - Gilliland, D. Gary
PY - 2008/9/1
Y1 - 2008/9/1
N2 - Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFpR, and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways. To identify the critical target genes required for transformation in hematopoietic cells, we used a comparative gene expression strategy in which selective small molecules were applied to 32Dcl3 cells that had been transformed to factor-independent growth by these respective oncogenic alleles. We identified inhibitor of DNA binding 1 (Id1), a gene involved in development, cell cycle, and tumorigenesis, as a common target of these oncogenic kinases. These findings were prospectively confirmed in cell lines and primary bone marrow cells engineered to express the respective tyrosine kinase alleles and were also confirmed in vivo in murine models of disease. Moreover, human AML cell lines Molm-14 and K562, which express the FLT3-ITD and BCR-ABL tyrosine kinases, respectively, showed high levels of Id1 expression. Antisense and siRNA based knockdown of Id1-inhibited growth of these cells associated with increased p27KiP1 expression and increased sensitivity to Trail-induced apoptosis. These findings indicate that Id1 is an important target of constitutively activated tyrosine kinases and may be a therapeutic target for leukemias associated with oncogenic tyrosine kinases.
AB - Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFpR, and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways. To identify the critical target genes required for transformation in hematopoietic cells, we used a comparative gene expression strategy in which selective small molecules were applied to 32Dcl3 cells that had been transformed to factor-independent growth by these respective oncogenic alleles. We identified inhibitor of DNA binding 1 (Id1), a gene involved in development, cell cycle, and tumorigenesis, as a common target of these oncogenic kinases. These findings were prospectively confirmed in cell lines and primary bone marrow cells engineered to express the respective tyrosine kinase alleles and were also confirmed in vivo in murine models of disease. Moreover, human AML cell lines Molm-14 and K562, which express the FLT3-ITD and BCR-ABL tyrosine kinases, respectively, showed high levels of Id1 expression. Antisense and siRNA based knockdown of Id1-inhibited growth of these cells associated with increased p27KiP1 expression and increased sensitivity to Trail-induced apoptosis. These findings indicate that Id1 is an important target of constitutively activated tyrosine kinases and may be a therapeutic target for leukemias associated with oncogenic tyrosine kinases.
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U2 - 10.1182/blood-2007-07-103010
DO - 10.1182/blood-2007-07-103010
M3 - Article
C2 - 18559972
AN - SCOPUS:52649174782
SN - 0006-4971
VL - 112
SP - 1981
EP - 1992
JO - Blood
JF - Blood
IS - 5
ER -