1. The Role of Nucleophosmin in Acute Myelogenous Leukemia Erik Olsson

2. What is AML? Acute myelogenous leukemia is a cancer of blood-forming tissues of the bone marrow. It is characterized by the growth of immature white blood cells. There are 8 categories of AML, categorized as M0 to M7, based on which blood cells are abnormal. MedlinePlus-U.S National Library of Medicine and The National Institutes of Health

3. What is AML?  Abnormal proliferation of myeloid precursors  Decreased rate of apoptosis and differentiation  The mutated cells rapidly replace normal blood cells  Accumulation of undifferentiated cells in bone marrow Advances in understanding the biology and genetics of acute myelocytic leukemia. Clin Lab Sci. 2005 Winter;18(1):28-37.

4. What is AML  Annual incidence of 2.4 per 100,000  40% survival rate >4% if over 65  If not treated death can occur within months  Chemotherapy and Bone Marrow Transplantation

5. Causes  Mutations in the ARF/p53 pathway  Chromosomal Translocations  Nucleophosmin is important in this pathway

6. Normal ARF/p53 Pathway  Multi-protein pathway of inhibitors ARF Mdm2 p53 NPM??

7. Grisendi, S., Pandolfi, P. P. (2005). NPM Mutations in Acute Myelogenous Leukemia. N Engl J Med 352: 291-292 Normal NPO Functions: Multifunctional phosphoprotein Normally accumulates in Nucleolus Control duplication of centrosome during cell cycle Interactions with tumor suppressor transcription factors ARF/p53 Pathway Negative Dominance NPM/B23 associates specifically with unduplicated centrosomes CDK2/Cyclin E

8. What goes Wrong? Chromosome Translocations Rearranged NPM encodes a fusion protein Deletion of part of Chromosome 5 often leads to oncogenesis Also frequently overexpressed in cancer Aberrant cytoplasmic localization

9. NPM/ARF/p53 Pathway NPM/ARF/p53 Pathway  Multi-protein pathway of inhibitors ARF Mdm2 p53 NPM

10. Negative Feedback Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function. Korgaonkar C, Hagen J, Tompkins V, Frazier AA, Allamargot C, Quelle FW, Quelle DE.

11. NPM-ARF Association Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function. Korgaonkar C, Hagen J, Tompkins V, Frazier AA, Allamargot C, Quelle FW, Quelle DE.

12. Summary  Nucleophosmin -Role in ARF/p53 Tumor Suppressor Pathway -Binds to ARF and prevents cytoplasmic localization -Overexpression has been implicated in many cancers Treatment???