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HOXA9 – HOXA9 –
Acute Acute
Myeloid Myeloid
LeukemiaLeukemia
HOX Genes encode transcription factors
http://en.wikipedia.org/wiki/Image:Homeodomain-dna-1ahd.png
The role of HOX Genes
• Universally specify
regional development
• Specify the
anterior-posterior axis
-Anteroposterior Development-
http://www.nybooks.com/images/tables/20060511012img1.jpg
http://evonet.sdsc.edu/evoscisociety/short/images/hox_gene.gif
What happens in development when you knockout a HOX gene?
**Anterior transformations**Development. Fromental-Ramain et al. 122 (2): 461
HOXA9 plays a key role inhematopoiesis
Normal development of hematopoietic cells
Knocking out HOXA9 disrupts T cell development
HOXA9 plays a key role inhematopoiesis
http://www.bloodlines.stemcells.com/img/Metcalf_Fig3_2.gif
Overexpress HOXA9 hematological malignancies
Acute Myeloid Leukemia (AML)
http://content.answers.com/main/content/wp/en-commons/2/20/Illu_blood_cell_lineage.jpg
Acute Myeloid Leukemia(AML)
• Replace bone marrow with primitive cells
• Differentiation arrest and
loss of apoptosis
• Immunosuppression infection death
Mechanisms by which HOXA9 is deregulated
Gene Translocation
Fusion Proteins
Deregulation of HOXA9
http://staff.jccc.net/PDECELL/evolution/mutations/translocation.gif
More on Translocations, Fusion Proteins
HOXA9-NUP98
A Potent Oncogene, Fusion Protein
• NUP98 is translocated next to HOXA9
• Translation creates HOXA9-NUP98 protein
Fusion Proteins induce proliferation and contribute to AML1. 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
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
More on Cofactors
• MEIS cofactors are synthesized with HOX proteins during embryogenesis
• Meis1a – routinely coactivated with HOXA9
Acute
Myeloid
Leukemia
Meis1a cofactor
Evert Kroon, et al. The EMBO Journal (1998) 17, 3714–3725
HOXA9 overexpression
Expression of Meis1a with HOXA9 accelerates Leukemogenesis in Mice
Evert Kroon, et al. The EMBO Journal (2001) 20, 350–361
Cofactor Meis1a intensifies proliferative effect of fusion protein NUP98-HOXA9
Evert Kroon, et al. The EMBO Journal (2001) 20, 350–361
Questions?