Targeting JAK3 and HOXA9 to Combat T-Cell ALL?

Researchers in Belgium are reporting new understanding regarding the development of acute lymphoblastic leukemia (ALL). Several cancer-causing genes had been previously identified, but now investigators have discovered how two specific cancer genes work together to trigger leukemia. Writing in Cancer Discovery, they report that JAK3/STAT5 mutations are important in ALL and may be targetable.

“Our study indicates that co-binding of STAT5 and HOXA9 at promoters of genes causes upregulation of those genes. One of these genes is PIM1, an oncogenic kinase. We demonstrate that the combination of JAK kinase inhibitors with PIM kinase inhibitors could be interesting to target these T-ALL (T-cell acute lymphoblastic leukemia) cases,” noted investigator Jan Cools, PhD, from the Laboratory for Molecular Biology of Leukemia VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.

The researchers focused on JAK3 mutations and overexpression of HOXA9. Cools said these two oncogenic events are frequently found together in T-ALL, and in much greater frequency than would occur by chance. The team found that coexpression of mutant JAK3 and HOXA9 could transform hematopoietic cells to exhibit cytokine-independent growth. This also induced leukemia development in vivo in a mouse model.

For their analysis, they examined the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression. Both of these events were identified as significantly co-occurring in T-ALL. The study showed that expression of both mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors. This was not the case with mutations of either JAK3 or HOXA9 alone.

“Mechanistically, we found that JAK3 activates the transcription factor STAT5, which binds DNA at the same locations as HOXA9 is also binding. Our data indicate that co-binding of STAT5 and HOXA9 at the same genes in the genome causes increased expression of these genes,” Cools explained.

He said it was surprising for the team to discover that STAT5 and HOXA9 co-occupy similar genetic loci. The team had hypothesized there would be a little overlap in binding, but were surprised by just how significant it was. Their identification of a direct cooperation between these two cancer genes paves the way for targeted treatments of T-ALL as well as other leukemias where JAK3/STAT5 is working in concert with HOXA9.

“When we study individual oncogenes, we do not see the big picture. It is important to study the combination of oncogenic events and determine how these oncogenic events cause cancer,” Cools emphasized. “Many oncogenes influence the behavior of other oncogenes, and that interaction could be a novel target for therapy.”