Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Henrike Jacobi; Margherita Vieri; Marlena Bütow; Carolina Y Namasu; Laura Flüter; Ivan G Costa; Tiago Maié; Katharina Lindemann-Docter; Nicolas Chatain; Fabian Beier; Michael Huber; Wolfgang Wagner; Martina Crysandt; Tim H Brümmendorf; Mirle Schemionek

doi:10.3389/fphar.2023.1212392

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Front Pharmacol. 2023 Jul 4:14:1212392. doi: 10.3389/fphar.2023.1212392. eCollection 2023.

Authors

Henrike Jacobi^{1

2}, Margherita Vieri^{1

2}, Marlena Bütow^{1

2}, Carolina Y Namasu¹, Laura Flüter¹, Ivan G Costa³, Tiago Maié³, Katharina Lindemann-Docter⁴, Nicolas Chatain^{1

2}, Fabian Beier^{1

2}, Michael Huber⁵, Wolfgang Wagner^{2

6

7}, Martina Crysandt^{1

2}, Tim H Brümmendorf^{1

2}, Mirle Schemionek^{1

2}

Affiliations

¹ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
² Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany.
³ Institute for Computational Genomics, RWTH Aachen University, Aachen, Germany.
⁴ Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
⁵ Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, Germany.
⁶ Helmholtz-Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
⁷ Institute for Stem Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.

Abstract

The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.

Keywords: CML; LSC; MSc; TFR; fibrosis; leukemic stem cells.

Grants and funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—428858226, 417911533 (in the framework of the Clinical Research Group “Untangling and Targeting Mechanisms of Myelofibrosis in Myeloproliferative Neoplasms (MPN)” CRU344), 331065168 (in the framework of the Research Training Group “Tumor-targeted Drug Delivery”) to MS and the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University (O3-5/531805) to MS and MH. This work was supported by the immunohistochemistry facility, a facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. Graphics were created with BioRender.com.