Deciphering fibrosis reversal mechanisms in chronic blood cancer for identification of novel predictive and therapeutic strategies

Introduction

Fibrosis is estimated to be involved in 45% of global mortality, and currently, no specific therapies for fibrosis in most organs exist. One central and controversially discussed question in the field of organ fibrosis is: “Is fibrosis truly reversible?” In Rewind-MF, I will address this biologically and clinically highly relevant question in a prime example: bone marrow fibrosis in a chronic blood cancer called Primary Myelofibrosis (PMF).

Background on PMF

In PMF, hematopoietic stem cells become mutated and activate fibrosis-driving cells. Fibrosis reversal in PMF is possible through allogeneic stem cell transplant (ASCT). However, the majority of patients are not eligible for this high-risk procedure. Alternative fibrosis-reversing strategies are not available, leaving this patient group without any treatment option.

Specific Aims

My specific aims in Rewind-MF are:

1. To gain spatio-temporal insights into fibrosis reversal and mutant clone elimination mechanisms to predict which patients will benefit from ASCT, and to identify therapeutic targets.
2. To understand how blood cancer is maintained in the bone marrow and later the spleen stroma in order to find new ways to reverse fibrosis and eradicate the cancer cells.
3. To validate fibrosis reversal mechanisms and translate them into clinically relevant therapeutic strategies.

Unique Approach

What makes Rewind-MF unique is the holistic “bench-to-bedside” approach starting from a stem cell biological hypothesis tested by innovative murine models and (stem) cell approaches. This is advanced by a broad interdisciplinary expertise with novel single-cell, spatial genomic, and computational technologies to dissect mechanisms of fibrosis reversal and develop therapeutic approaches that go beyond pure target identification.

Integration of Technologies

The integration of all these technologies in clinically relevant specimens with follow-up data and large independent validation cohorts will truly revolutionize the prognostication and personalized treatment of patients with MF.