HOXA9 Mutation In Acute Myeloid Leukemia

By Walton Gibbons

Leukemia and Specifically AML

• Leukemia is the unregulated proliferation of hematopoietic (blood forming) stem cells

• Acute Myeloid Leukemia (AML) affects granulocytes, monocytes and platelets

• These cells replace normal hematopoietic tissue in the bone marrow

AML

• Can occur in adults and children

• 50% of adult leukemias

• Results in fatigue and weakness due to failure of bone marrow

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HOX genes

Molecular Biology Of the Cell FIG 21-45

What are HOX Genes?

• Family of transcription factors

• Each directs fate of specific body regions

• Order of genes on chromosome is colinear with expression along anterior/posterior axis

Common Patterns of Development

- Hox genes direct development of different body segments

- First genes on chromosome expressed most anterior and later genes expressed more posterior

Molecular Cell Biology FIG 1-12

HOX A9

• Mammals have four HOX clusters, whereas Drosophila has only one

• “A” = the first cluster, and “9” = the 9th gene

• Human HOXA9 maps to chromosome 7p15

Research• Conservation through evolution allows for Hox

genes of mice to be studied, since they’re virtually identical to human HOX genes

Molecular Biology of The Cell FIG 21-46

Biological Function of HOXA9

• Determine by doing genetics...

1. Mutation in which NO Hoxa9 is present

2. Mutation in which Hoxa9 is overexpressed

Hoxa9-/- Mutant Mice

Hoxa9-/- mutant mice had lumbar vertebrae L1 to L5 become more anterior

Fromental-Ramain et al.

Fromental-Ramain et al.

Combining Mutants

• Double mutant of Hoxa9-/- and Hoxd9-/-

1. More penetrant abnormalities

2. New limb alterations

3. Additional axial skeleton transformations

*Both specific and redundant functions

HOXA9 and Hematopoiesis

• Hoxa9-/- mice - disrupted hematopoiesis with a decrease in lymphocytes and granulocytes

• Overexpression of Hoxa9 in mice –

-defective T-cell development

-dysfunctional hematopoiesis

-leads to AML

Overexpression of HOXA9

• Leukemic cells from humans have provided evidence that overexpression of HOXA9 as well as other HOX genes is at least partly involved in transformation

• Studies on NIH3T3 cells with enforced expression of HOXA9 protein show increases in transformation and eventually lead to AML if implanted in mice

Chromosomal Translocation

• AML cases often have a chromosomal translocation t(7;11)(p15;p15)

• Involves the breaking and rejoining of NUP98 gene with HOXA9

Co-Activational Transcription Factors

• There is a strong correlation between activation of Hoxa9 and several other proteins including:

- MEIS

- PBX

Transcriptional Activation and Repression

- Chromosomal translocations in human leukemias often cause high activation of HOX genes leading to inappropriate transcription of downstream targets

- In the same sense, overexpression of these HOX genes may lead to production of a protein which INHIBITS transcription of downstream target genes

Owens, Hawley

CONCLUSION

- Overexpression of HOXA9 is strongly correlated with human AML

- Future goal = find the target genes regulated by HOX proteins in normal hematopoietic development

Acknowledgements

• Owens B., Hawley R. HOX and Non-HOX Homeobox Genes in Leukemic Hematopoiesis

• Fromental-Ramain et al. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning

• Gilliland G., Jordan C., and Felix C. The Molecular Basis of Leukemia

• www.emedicine.com/derm/topic924.html• mcb.asm.org/cgi/content/full/20/9/3274