1. HOXA9 – AcuteMyeloidLeukemia

2. HOX Genes encode transcription factors http://en.wikipedia.org/wiki/Image:Homeodomain-dna-1ahd.png

3. The role of HOX Genes Universally specify regional development Specify the anterior-posterior axis -Anteroposterior Development- http://www.nybooks.com/images/tables/20060511012img1.jpg

4. http://evonet.sdsc.edu/evoscisociety/short/images/hox_gene.gif

5. What happens in development when you knockout a HOX gene? **Anterior transformations** Development. Fromental-Ramain et al. 122 (2): 461

6. HOXA9 plays a key role in hematopoiesis Normal development of hematopoietic cells

7. Knocking out HOXA9 disrupts T cell development HOXA9 plays a key role in hematopoiesis http://www.bloodlines.stemcells.com/img/Metcalf_Fig3_2.gif

8. Overexpress HOXA9  hematological malignancies Acute Myeloid Leukemia (AML) http://content.answers.com/main/content/wp/en-commons/2/20/Illu_blood_cell_lineage.jpg

9. Acute Myeloid Leukemia (AML) Replace bone marrow with primitive cells Differentiation arrest and loss of apoptosis Immunosuppression  infection  death

10. Mechanisms by which HOXA9 is deregulated Gene Translocation Fusion Proteins Deregulation of HOXA9 http://staff.jccc.net/PDECELL/evolution/mutations/translocation.gif

11. More on Translocations, Fusion Proteins HOXA9-NUP98 A Potent Oncogene, Fusion Protein NUP98 is translocated next to HOXA9 Translation creates HOXA9-NUP98 protein

12. Fusion Proteins induce proliferation and contribute to AML 1. Express NUP98-HOXA9  Transformation of myeloblasts (progenitor cells) 2. Transplant the transformed cells to bone marrow of healthy mice  AML onset Evert Kroon, et al. The EMBO Journal (2001) 20, 350–361

13. Mechanisms by which HOXA9 contributes to cancer (Part 2) non-HOX genes can serve as cofactors Accelerated leukemogenesis How?? 1. Alter properties of HOXA9 proteins 2. Promotes overexpression of HOXA9

14. More on Cofactors MEIS cofactors are synthesized with HOX proteins during embryogenesis Meis1a – routinely coactivated with HOXA9

15. Acute Myeloid Leukemia Meis1a cofactor Evert Kroon, et al. The EMBO Journal (1998) 17, 3714–3725 HOXA9 overexpression

16. Expression of Meis1a with HOXA9 accelerates Leukemogenesis in Mice Evert Kroon, et al. The EMBO Journal (2001) 20, 350–361

17. Cofactor Meis1a intensifies proliferative effect of fusion protein NUP98-HOXA9 Evert Kroon, et al. The EMBO Journal (2001) 20, 350–361

18. Questions?