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)

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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?