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