1 / 18

HOXA9 – Acute Myeloid Leukemia

HOXA9 – Acute Myeloid Leukemia. HOX Genes encode transcription factors. http://en.wikipedia.org/wiki/Image:Homeodomain-dna-1ahd.png. The role of HOX Genes. -Anteroposterior Development-. Universally specify regional development Specify the anterior-posterior axis.

ilana
Download Presentation

HOXA9 – Acute Myeloid Leukemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HOXA9 – Acute Myeloid Leukemia

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

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

  4. http://evonet.sdsc.edu/evoscisociety/short/images/hox_gene.gifhttp://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 inhematopoiesis Normal development of hematopoietic cells

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

  8. Acute Myeloid Leukemia (AML) Overexpress HOXA9  hematological malignancies 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. HOXA9 overexpression Meis1a cofactor Acute Myeloid Leukemia Evert Kroon, et al. The EMBO Journal (1998) 17, 3714–3725

  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?

More Related