Sheri T Dorsam, Christina M Ferrell, Glenn P Dorsam, Mika K Derynck, Ulka Vijapurkar, Daniel Khodabakhsh, Bonnie Pau, Hillary Bernstein, Christopher M Haqq, Corey Largman, and H J Lawrence*

Department of Medicine, University of San Francisco, San Francisco, CA, USA; Department of Medicine,
Veterans Affairs Medical Center, San Francisco, CA, USA; UCSF Comprehensive Cancer Center, San
Francisco, CA, USA

* Corresponding author;     email: jeffl@medicine.ucsf.edu

Hematopoietic defects in HOXA9 ^-/- mice demonstrate a key role for this homeoprotein in blood cell
development. Conversely, enforced HOXA9 expression is leukemogenic in mice, and HOXA9 is frequently
activated in human acute myeloid leukemia (AML). While HOXA9 is thought to function as a transcription
factor, few downstream targets have been identified. We searched for early HOXA9 target genes by using a
transient over-expression strategy in three hematopoietic cell lines (2 myeloid, 1 lymphoid). cDNA microarray
analyses identified 220 genes whose expression was modulated at least two-fold. Expression signatures in
myeloid and lymphoid cells demonstrated that HOXA9 functions as both an activator and repressor of a variety
of genes in cell-specific patterns suggesting that the transcriptional effects of HOXA9 are largely cell-context
dependent. Transient transcription assays and target gene expression patterns in HOXA9 ^-/- marrow cells imply
that we have identified direct physiologic targets. Many target genes are expressed in CD34 ⁺ stem cells and/or
are members of gene families involved in proliferation or myeloid differentiation. Expression of fourteen
HOXA9 target genes correlated with high level HOXA9 expression in primary AML. These data suggest that
many genes identified in this survey may mediate the biologic effects of HOXA9 in normal and leukemic
hematopoiesis.

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