Bcr-Abl induces autocrine IGF-1 signaling.
Bcr-Abl oncogene is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the Bcr-Abl inhibitor imatinib. Over time patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that Riz1 expression decreases in blast crisis and that re-expression of Riz1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. We observed that in 8 out of 11 matched CML patient biopsies the IGF-1 expression is elevated in blast crisis. We examined mechanisms used by CML blast crisis cell lines to activate IGF-1 expression. We found that Bcr-Abl activates autocrine IGF-1 signaling using Hck and Stat5b. Inhibition of these signaling components using small molecule drugs or shRNA decreases proliferation and enhances apoptosis. Together, our study suggests that aberrant IGF-1 signaling is an important event in blast crisis transformation and it provides a mechanism to explain the activity of IGF-1R and Hck inhibitors in blocking CML blast crisis phenotypes.
Lakshmikuttyamma
A
A
Genomic Medicine and Pathobiology Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Pastural
E
E
Takahashi
N
N
Sawada
K
K
Sheridan
D P
DP
DeCoteau
J F
JF
Geyer
C R
CR
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001752:Blast Crisis; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D010879:Piperazines / Q000627:therapeutic use; D051572:Proto-Oncogene Proteins c-hck / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D007334:Insulin-Like Growth Factor I; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck