Abstract

t(8;21) is one of the most common chromosomal abnormalities associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion protein is directly involved in the pathogenesis of AML but is not able to cause leukemia on its own. We have shown previously that a C-terminal splice variant of t(8;21), AML1-ETO9a (AE9a), is sufficient to promote AML in mice. Here we show that the leukemia-initiating cells reside in the Lin-/Sca1-/cKit+ population. To identify molecular targets directly modulated by AE9a, we compared the gene expression profile to the promoter occupancy (ChIP-on-chip) profile of this population. We identified 1485 genes deregulated by AE9a, among which 544 genes are also ChIP-on-chip targets. CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, was greatly down-regulated in AE9a leukemia cells. We further show that t(8;21) AML-M2 patient samples have lower CD45 levels compared to non-t(8;21) AML-M2 samples. Interestingly, JAK1 and JAK2 were upregulated by AE9a and both CD45 and JAK1 are ChIP-on-chip targets. In addition we show that JAK/STAT signaling was enhanced in the leukemia cells. Consequently, the leukemia cells are more susceptible to JAK2 inhibitors than wild type cells. Our results indicate that AE9a enhances JAK/STAT signaling by directly modulating regulators of this signaling pathway, which provides a potential novel approach to treating t(8;21) AML.

Disclosures: No relevant conflicts of interest to declare.

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