Do “driver” mutations really come first in myelofibrosis?

Written by Kristin Bundy for Scroll Health Studio

Researchers look deeper into the role of inflammation.

Pinpointing the pathogenesis of myelofibrosis (MF) has been described as a chicken-or-the-egg scenario. Chronic inflammation and the JAK2 clone have become so intertwined in the literature, researchers have questioned which comes first.

But the latest research suggests inflammation plays a central role in MF whether a JAK mutation exists or not. “In cancer, we generally think that the mutant cell is the whole problem, and therefore the target,” says Angela Fleischman, associate professor of hematology/oncology at University of California Irvine. “But in myeloproliferative neoplasms [MPNs], getting rid of the clone doesn’t fix the problem.” The JAK2 clone, at least in some people, she says, is a consequence and not necessarily the root cause of MF.

Dr Fleischman and others, including John Mascarenhas, professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, describe chronic inflammation in MF as the overproduction of multiple inflammatory cytokines and the dysregulation of many anti-inflammatory processes, which drive disease and symptom heterogeneity.

Centering inflammation in MF pathogenesis upends the years-long focus of JAK as the driver of disease, says Dr Mascarenhas. “Now, we realize that there are other pathways that are relevant—pathways that are complementary or additive to the disease phenotype.”

JAK-STAT–independent pathways that activate the immune regulator known as nuclear factor kappa B, or NFκB, have been the focus of investigation. One pathway in particular, TLR/IL1R-IRAK, has risen to the top as a main signaling pathway responsible for inflammatory cytokine production. Another pathway suspected to play a role in MF inflammation is RhoA-ROCK.

“As we learn and understand MF heterogeneity—which pathways are relevant and which areas to target—it’s going to change the paradigm of how we treat patients,” says Dr Mascarenhas. “It won’t be one-drug-fits-all.” Dr Fleischman concurs: “Each myelofibrosis patient is unique. What works for one patient may not work for another. That’s why we need new treatments with different targets.”