Novel Approaches Needed to Mitigate Myelofibrosis Persistence, Say Researchers

Despite offering benefits for patients with myelofibrosis, JAK2 inhibitors like ruxolitinib do not significantly impact the abnormal hematopoietic clone, resulting in a persistence of myelofibrosis; but, novel approaches to targeting JAK2 could prove beneficial for patients with the disease, say researchers of a new paper.

Ruxolitinib has been shown to reduce splenomegaly and improve various symptoms of myelofibrosis but does not eliminate the mutant clonal population of cells. The JAK1/JAK2 tyrosine kinase inhibitor is a type 1 inhibitor of JAK2, which binds to the active conformation of the enzyme. The researchers explain that this leads JAK2 to become resistant to degradation with consequent accumulation of phosphor-JAK2, which can result in myelofibrosis persistence.

According to the researchers, various explanations have been suggested as the reasoning behind ruxolitinib persistence, including the activation of alternative kinases not inhibited by the treatment, epigenetic mutations resulting in growth advantage, phosphatase negative feedback inhibition, lack of specificity for JAK2 V617F versus wild-type JAK2, and the accumulation of p-JAK2 during exposure to treatment.

“Despite the symptomatic benefits of currently available JAK2 inhibitors, there is a need for agents that have a greater effect on the disease clone and its natural history,” explained the researchers. “JAK2 remains a crucial target in myelofibrosis, and deletion of JAK2 in a mouse model of myelofibrosis substantially abrogates disease manifestations. Data from several groups have shown that a conformational change in JAK2 induced by the binding of ruxolitinib and other type 1 inhibitors may contribute to disease persistence by preventing JAK2 de-phosphorylation and proteasomal degradation, allowing heterodimerization of JAK2 with JAK1 or TYK2.”

The researchers note that, to date, all JAK2 inhibitors that have been tested have been type 1 inhibitors.

However, they explain that type 2 inhibitors like BCR-ABL1 inhibitor imatinib, on the other hand, do not seem to result in persistence of disease. In one mouse model, the inhibitor type was shown to also have a greater effect on disease biology.

“The V617F mutation leads to a highly inflexible substitution, which may be indicative of a neo- morphic change in function, rather than non-specific over-activation,” wrote the researchers. “Several lines of evidence suggest that it may be possible to exploit the unique properties of the mutant pseudokinase to develop mutation-specific JAK2 inhibitors that spare normal hematopoiesis.”

Reference

Ross D, Babon J, Tvorogov D, Thomas D. Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications. Haematologica. 2021;106(5):1244-1253. doi: 10.3324/haematol.2020.262691