Research · IL-1 · Inflammation
Chronic inflammation as a driver of clonal expansion.
Targeting the IL-1 axis in MPN.
JAK inhibitors manage MPN symptoms but don't reverse fibrosis or eliminate the mutant clone. We identified IL-1 signaling as a key driver of clonal expansion and bone marrow fibrosis, and showed that IL-1R1 antibody blockade reduces disease burden in murine MPN.
Patients with myeloproliferative neoplasms live with chronic systemic inflammation: bone pain, fatigue, fevers, splenomegaly. Current JAK inhibitors blunt the symptoms but leave the underlying clone and the marrow scarring largely intact. If inflammation isn't a side effect but a driver, then targeting it could be the missing half of treatment.
Patients with MPN show elevated circulating inflammatory cytokines, and the JAK2V617F-mutant clone exists inside a bone marrow niche that becomes progressively more inflammatory as disease advances. The lab's hypothesis was that this isn't only a consequence of the disease but part of what sustains it.
Using the inducible JAK2V617F knock-in model, the lab showed that IL-1 signaling is markedly elevated and that genetic loss of IL-1 in the JAK2V617F context reduces clonal expansion and slows bone marrow fibrosis. Antibody blockade of IL-1R1 reproduces the genetic phenotype: less competitive advantage for the mutant clone, less fibrotic remodeling, less disease burden.
Mechanistically, IL-1 functions as a microenvironmental amplifier. The mutant clone produces IL-1; supporting stromal and immune cells respond to IL-1; the response feeds back to support the mutant clone's expansion and the deposition of marrow scar. Cutting that loop is the therapeutic premise.
What the lab has shown directly, with anchors to the published papers.
- 01
IL-1 signaling drives clonal expansion of JAK2V617F-mutant cells.
- 02
IL-1R1 antibody blockade reduces bone marrow fibrosis in murine MPN.
- 03
IL-1 inhibition complements JAK2 inhibition mechanistically.
Will IL-1 inhibitors combine well with JAK inhibitors in patients? What's the exact cellular source of IL-1 in the MPN bone marrow — and does targeting that source give the clone fewer escape routes than blocking the cytokine itself? An active R21 NCI award funds the preclinical answer.
01
PMID 36100596 ↗2022Nature Communications13(1):5347
Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm
Rahman MF, Yang Y, Le BT, Dutta A, Posyniak J, Faughnan P, Sayem MA, Aguilera NS, Mohi G
The full archive
The complete bibliography lives on the publications page.
Lab page on UVA BMG: Research themes ↗ · Contact: gm7sj@virginia.edu