Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.
Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFbetaR, 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 p27(Kip1) 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.
Hematology Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Winnie F
WF
Tam
Ting-Lei
TL
Gu
Jing
J
Chen
Benjamin H
BH
Lee
Lars
L
Bullinger
Stefan
S
Fröhling
Andrew
A
Wang
Stefano
S
Monti
Todd R
TR
Golub
D Gary
DG
Gilliland
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001549:Benzamides; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D051798:Inhibitor of Differentiation Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009857:Oncogenes; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001549:Benzamides; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; C464670:tandutinib; D011505:Protein-Tyrosine Kinases