title: Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease.
abstract: Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO-deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3-kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML-derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K-dependent ICSBP phosphorylation.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Melissa Kristine
authors.initials: MK
authors.lastname: Middleton
authors.forename: Alicia Marie
authors.initials: AM
authors.lastname: Zukas
authors.forename: Tanya
authors.initials: T
authors.lastname: Rubinstein
authors.forename: Michele
authors.initials: M
authors.lastname: Jacob
authors.forename: Peijuan
authors.initials: P
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Ian
authors.initials: I
authors.lastname: Blair
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D022423:Myeloid Cells / Q000201:enzymology / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*
chemical_list: C475064:12-15-lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase