title: IGF signaling contributes to malignant transformation of hematopoietic progenitors by the MLL-AF9 oncoprotein.
abstract: Malignant transformation of normal hematopoietic progenitors is a multistep process that likely requires interaction between collaborating oncogenic signals at critical junctures. For instance, the MLL-AF9 fusion oncogene is thought to contribute to myeloid leukemogenesis by driving a hematopoietic stem cell-like "self-renewal" gene expression signature in committed myeloid progenitors. In addition, insulin-like growth factor (IGF) signaling has been implicated in self-renewal/pluripotency in hematopoietic and embryonic stem cell contexts and supports cell growth/survival by activation of downstream pathways, including phosphatidylinositol 3-kinase/Akt and Ras/Raf/extracellular signal-regulated kinase. We hypothesized that IGF signaling could be an important contributor in the process of cellular transformation and/or clonal propagation. Utilizing an MLL-AF9 mouse bone marrow transplantation model of acute myelogenous leukemia, we discovered that committed myeloid progenitor cells with genetically reduced levels of IGF1R were less susceptible to leukemogenic transformation due, at least in part, to a cell-autonomous defect in clonogenic activity. Rather unexpectedly, genetic deletion of IGF1R by inducible Cre recombinase had no effect on growth/survival of established leukemia cells. These findings suggest that IGF1R signaling contributes to transformation of normal myeloid progenitor cells, but is not required for propagation of the leukemic clone once it has become established. We also show that treatment of mouse MLL-AF9 acute myelogenous leukemia cells with BMS-536924, an IGF1R/insulin receptor-selective tyrosine kinase inhibitor, blocked cell growth, suggesting its efficacy in this model may be due to inhibition of insulin receptor and/or related tyrosine kinases, and raising the possibility that similar IGF1R inhibitors in clinical development may be acting through alternate/related pathways.
authors.affiliation: Terry Fox Laboratory/Department of Pathology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Jenkins
authors.forename: Olena O
authors.initials: OO
authors.lastname: Shevchuk
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.forename: Sonya H
authors.initials: SH
authors.lastname: Lam
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D014227:Triazines / Q000494:pharmacology
chemical_list: C504983:BMS 536924; C545990:BMS 754807; D001562:Benzimidazoles; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011728:Pyridones; D014227:Triazines; D017526:Receptor, IGF Type 1