The Journal of Experimental Medicine
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Published online 16 October 2006 doi:10.1084/jem.20061444
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 11, 2529-2540
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ARTICLE

 Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease

Melissa Kristine Middleton1,2, Alicia Marie Zukas1, Tanya Rubinstein1, Michele Jacob1, Peijuan Zhu3,4, Liang Zhao1, Ian Blair3,4, and Ellen Puré1,2,5

1 The Wistar Institute, Philadelphia, PA 19104
2 Immunology Graduate Group, 3 Center for Cancer Pharmacology, and 4 Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104
5 The Ludwig Institute for Cancer Research, Philadelphia, PA 19104

CORRESPONDENCE Ellen Puré: pure{at}wistar.org

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.

Abbreviations used: 12/15-LO, 12/15-lipoxygenase; CML, chronic myelogenous leukemia; H&E, hematoxylin and eosin; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HpETE, hydroperoxyeicosatetraenoic acid; ICSBP, interferon consensus sequence binding protein; IRF-8, interferon regulatory factor 8; MPD, myeloproliferative disease; PI3-K, phosphatidylinositol 3–kinase.


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