Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients
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....
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1212392/full |
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| author | Henrike Jacobi Henrike Jacobi Margherita Vieri Margherita Vieri Marlena Bütow Marlena Bütow Carolina Y. Namasu Laura Flüter Ivan G. Costa Tiago Maié Katharina Lindemann-Docter Nicolas Chatain Nicolas Chatain Fabian Beier Fabian Beier Michael Huber Wolfgang Wagner Wolfgang Wagner Wolfgang Wagner Martina Crysandt Martina Crysandt Tim H. Brümmendorf Tim H. Brümmendorf Mirle Schemionek Mirle Schemionek |
| author_facet | Henrike Jacobi Henrike Jacobi Margherita Vieri Margherita Vieri Marlena Bütow Marlena Bütow Carolina Y. Namasu Laura Flüter Ivan G. Costa Tiago Maié Katharina Lindemann-Docter Nicolas Chatain Nicolas Chatain Fabian Beier Fabian Beier Michael Huber Wolfgang Wagner Wolfgang Wagner Wolfgang Wagner Martina Crysandt Martina Crysandt Tim H. Brümmendorf Tim H. Brümmendorf Mirle Schemionek Mirle Schemionek |
| author_sort | Henrike Jacobi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T01:32:43Z |
| format | Article |
| id | doaj.art-1bcfdb9e48a74693a9367baef6ba229c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T01:32:43Z |
| publishDate | 2023-07-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-1bcfdb9e48a74693a9367baef6ba229c2023-07-04T06:39:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-07-011410.3389/fphar.2023.12123921212392Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patientsHenrike Jacobi0Henrike Jacobi1Margherita Vieri2Margherita Vieri3Marlena Bütow4Marlena Bütow5Carolina Y. Namasu6Laura Flüter7Ivan G. Costa8Tiago Maié9Katharina Lindemann-Docter10Nicolas Chatain11Nicolas Chatain12Fabian Beier13Fabian Beier14Michael Huber15Wolfgang Wagner16Wolfgang Wagner17Wolfgang Wagner18Martina Crysandt19Martina Crysandt20Tim H. Brümmendorf21Tim H. Brümmendorf22Mirle Schemionek23Mirle Schemionek24Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyInstitute for Computational Genomics, RWTH Aachen University, Aachen, GermanyInstitute for Computational Genomics, RWTH Aachen University, Aachen, GermanyInstitute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyInstitute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyHelmholtz-Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyInstitute for Stem Cell Biology, RWTH Aachen University Medical School, Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyDepartment of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, GermanyCenter for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, GermanyThe 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1212392/fullCMLTFRfibrosisleukemic stem cellsLSCMSc |
| spellingShingle | Henrike Jacobi Henrike Jacobi Margherita Vieri Margherita Vieri Marlena Bütow Marlena Bütow Carolina Y. Namasu Laura Flüter Ivan G. Costa Tiago Maié Katharina Lindemann-Docter Nicolas Chatain Nicolas Chatain Fabian Beier Fabian Beier Michael Huber Wolfgang Wagner Wolfgang Wagner Wolfgang Wagner Martina Crysandt Martina Crysandt Tim H. Brümmendorf Tim H. Brümmendorf Mirle Schemionek Mirle Schemionek Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients Frontiers in Pharmacology CML TFR fibrosis leukemic stem cells LSC MSc |
| title | Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients |
| title_full | Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients |
| title_fullStr | Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients |
| title_full_unstemmed | Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients |
| title_short | Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients |
| title_sort | myelofibrosis at diagnosis is associated with the failure of treatment free remission in cml patients |
| topic | CML TFR fibrosis leukemic stem cells LSC MSc |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1212392/full |
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