In a study published in Blood, investigators sought to define a new therapeutic target for the treatment of myelofibrosis (MF), which could potentially lead to a new treatment that targets MF clones, as opposed to treating the symptoms of MF.
“Although JAK1/2 inhibition is effective into alleviating symptoms of MF, it does not result in the eradication of MF clones, which can lead to inhibitor-resistant clones emerging during the treatment,” the authors explained.
In this study, the researchers developed a preclinical model of induced pluripotent cells from MF patient samples that harbored the following mutations: JAK2 V617F, CALR type 1, or CALR type 2.
These cells were then used for chemical screening, which identified calcium/calmodulin-dependent protein kinase 2 (CAMK2) as a promising therapeutic target.
Next, MF model cells and mice induced by MPL W515L, another type of mutations recurrently detected in MF patients, were used to elucidate the therapeutic potential of CAMK2 inhibition. The researchers found that CAMK2 inhibition was effective against JAK2 inhibitor-sensitive and JAK2 inhibitor-resistant cells, and additional investigation revealed CAMK2 gamma subtype was important in MF model cells induced by MPL W515L.
They added that CAMK2G inhibition with berbamine, a CAMK2G inhibitor, significantly prolonged survival and reduced disease phenotypes such as splenomegaly and leukocytosis in the mouse model induced by MPL W515L.
“We investigated the molecular mechanisms underlying the therapeutic effect of CAMK2G inhibition and found that CAMK2G is activated by MPL signaling in MF model cells and is an effector in the MPL-JAK2 signaling pathway in these cells,” the authors concluded. “These results indicate CAMK2G plays an important role in MF, and CAMK2G inhibition may be a novel therapeutic strategy that overcomes resistance to JAK1/2 inhibition.”