by ecancer reporter Janet Fricker

There is “no biological rationale” for using JAK2 inhibitors in Chronic Myeloid Leukaemia (CML) patients, concludes a knock-out mouse model study published in Nature Chemical Biology.

In CML the formation of the BCR-ABL oncoprotein is considered a defining molecular event with targeted drugs, such as imatinib, inhibiting the resulting tyrosine kinase.

A number of patients, however, experience resistance to imatinib leading to the need for alternative approaches to treatment. The activation of the gene regulatory factor STAT5, which in normal and some malignant cell types is activated by the kinase JAK2, represents another important event in CML. JAK2 TKIs are an emerging class of compounds  that are currently receiving attention from the research community, with several in clinical trials.

In the current study Giulio Superti-Furga and colleagues, from the Austrian Academy of Sciences (Vienna, Australia), used JAK2 knock-out mice to investigate the mechanism of action of JAK2 TKIs in BCR-ABL induced STAT5 activation. To undertake this research the team had been able to overcome the embryonic lethality of the conventional JAK2 knockout mouse model.

The investigators were able to show that once a transformed phenotype had been established by the expression of different ABL oncoproteins, the growth and phenotypic characteristics of cells in vivo did not differ regardless of JAK2 expression.

“Collectively, our data show that JAK2 is not a drug target in CML,” write the authors. Future attempts to improve treatment of BCR-ABL TKI-resistant patients, they add, should instead focus on inhibition of STAT5. “This is the logical next step in the cascade downstream of BCR-ABL.”

Reference

O. Hantschel, W. Warsch, E. Eckelhart et al. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukaemia. Nature Chemical Biology. doi: 10.1038/NChemBio.775