Inhibition of JAK2VF Signaling by TL-895: A Potential Therapeutic Approach for Myeloproliferative Neoplasms

Myelofibrosis (MF) is a hematopoietic disorder featuring JAK2 pathway dysregulation, leading to symptoms like splenomegaly. While ruxolitinib can alleviate these symptoms, treatment is often constrained by loss of efficacy, adverse effects, and disease progression. There is an unmet need for novel therapies that can modify the disease course.

TL-895 is an orally available small molecule inhibitor of BTK and BMX, currently under investigation for its potential to impede abnormal cell adhesion and trafficking in MF patients, ameliorate cytokine-driven symptoms, and enhance megakaryopoiesis.

The study aimed to evaluate TL-895's impact on signaling, cell adhesion, and chemotaxis in JAK2VF cells. Cells expressing JAK2WT and JAK2VF were treated with TL-895, ibrutinib, or ruxolitinib, and intracellular signaling was assessed. Adhesion assays on ICAM or VCAM-coated plates and trans-well motility assays using SDF1α as a chemo-attractant were conducted. RAC1 activation was measured to understand its role in cell movement.

The results indicated that TL-895 effectively reduced BTK pathway activation in JAK2VF cells. It also significantly blocked cell adhesion on VCAM and ICAM surfaces and inhibited chemotaxis toward SDF1α. Additionally, TL-895 treatment decreased RAC1 activation, suggesting its role in influencing cell adhesion and movement.

The study concludes that TL-895's inhibition of BTK signaling could disrupt the interaction of JAK2VF myeloblasts with the microenvironment, potentially improving MF patient outcomes. Clinical trials are underway to test this hypothesis.