Acute Promyelocytic Leukemia (APL) is associated with reciprocal translocations which involve the RARa locus on chromosome 17 which variably translocates and fuses to the PML, PLZF, NPM or NuMA genes (for brevity referred to as X genes/proteins). In all cases, due to the reciprocity of the translocation, two fusion genes are generated encoding X-RARa and RARa-X fusion proteins. We hypothesize that X-RARa and RARa-X act to interfere with the normal transcriptional function of RARa and the biological function of X proteins, and that X proteins thus play a key role in oncogenesis. We propose to test the above hypothesis and study the function of the X genes in both APL and human cancer pathogenesis with the following Specific Aims: 1) To define the molecular basis underlying PML tumor suppressive activity and the aberrant mechanism(s) that causes its loss in human cancer. We determined in knock-out (KO) mice and cells that nuclear isoforms of PML exerts key tumor suppressive functions. More recently, we discovered that PML also acts in the cytosol through isoforms devoid of a nuclear localization signal (cytoplasmic PML: cPML). However, to date no biochemical discrete function has been attributed to PML. We also demonstrated that PML is frequently lost in multiple prevalent human cancers. We propose to study whether PML displays a specific intrinsic enzymatic activity; to determine the mechanisms of PML loss in human cancer; and to further investigate the biological function of cPML. 2) To determine the role of PLZF and its homologue PLZP in hemopoietic stem cell (HSC), leukemia stem cell (LSC) biology and leukemogenesis. We showed in KO mice that Plzf exerts important developmental and tumor/growth suppressive functions. Recently, we determined that Plzf is critical for the quiescence and maintenance of the stem cell compartment. We will test whether Plzf is essential for the self-renewal capabilities of LSCs of acute myeloid leukemia (AML) subtypes and for the generation of quiescent long term (LT) - LSCs that are key to disease relapse. We will study hematopoiesis and HSC compartment biology in Plzf/Plzp double KO mutants, which we have recently generated. Lastly, we-will assess both in vitro and in vivo the functional relevance of an emerging negative cross talk between Plzf and Pokemon. 3) To determine the role of NPM in tumor suppression, myelodysplastic syndrome (MDS) and leukemia pathogenesis. We have generated a Npm hypomorphic/KO allelic series in the mouse and found that Npm inactivation results in cancer susceptibility. Importantly, Npm+l- mice spontaneously develop a MDS-like syndrome. We will determine the mechanisms by which Npm exerts its tumor suppressive function focusing oh the cross talk between Npm and the Arf/p53 pathway. We will study the role of NPM in MDS pathogenesis in Npm+l- cells/mice, in Npm conditional mutants, in mice concomitantly lacking Npm and other candidate genes, on 5q and in human MDS samples. 4) To define in KO mice the role of NuMA in ontogenesis, hemopoiesis and oncogenesis. We will characterize Numa complete and conditional KO mice to investigate its role in development and hemopoiesis. Numa-/- primary cells (e.g. mouse embryonic fibroblasts) and Numa mouse mutants will be employed to study the role of this gene in tumorigenesis. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Yassin, Rihab R,
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Sloan-Kettering Institute for Cancer Research
New York
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Khanna-Gupta, Arati; Abayasekara, Nirmalee; Levine, Michelle et al. (2012) Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein ? activity: implications in myelodysplastic syndrome and acute myeloid leukemia. J Biol Chem 287:32728-37
Cheng, Ke; Sportoletti, Paolo; Ito, Keisuke et al. (2010) The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 115:3341-5
Ito, Keisuke; Bernardi, Rosa; Pandolfi, Pier Paolo (2009) A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Curr Opin Genet Dev 19:51-9
Ito, Keisuke; Bernardi, Rosa; Morotti, Alessandro et al. (2008) PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453:1072-8
Sportoletti, Paolo; Grisendi, Silvia; Majid, Samia M et al. (2008) Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111:3859-62
Costoya, J A; Hobbs, R M; Pandolfi, P P (2008) Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation. Oncogene 27:3789-96
Salomoni, P; Guernah, I; Pandolfi, P P (2006) The PML-nuclear body associated protein Daxx regulates the cellular response to CD40. Cell Death Differ 13:672-5
Bernassola, Francesca; Oberst, Andrew; Melino, Gerry et al. (2005) The promyelocytic leukaemia protein tumour suppressor functions as a transcriptional regulator of p63. Oncogene 24:6982-6
Salomoni, Paolo; Bernardi, Rosa; Bergmann, Stephan et al. (2005) The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105:3686-90
Bernassola, Francesca; Salomoni, Paolo; Oberst, Andrew et al. (2004) Ubiquitin-dependent degradation of p73 is inhibited by PML. J Exp Med 199:1545-57

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