PMID- 33089365 OWN - NLM STAT- MEDLINE DCOM- 20210113 LR - 20210113 IS - 1432-0584 (Electronic) IS - 0939-5555 (Linking) VI - 100 IP - 1 DP - 2021 Jan TI - Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis. PG - 105-116 LID - 10.1007/s00277-020-04306-w [doi] AB - Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients. FAU - Rambaldi, Benedetta AU - Rambaldi B AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. AD - Department of Hematology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. AD - Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. FAU - Diral, Elisa AU - Diral E AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. AD - Department of Hematology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. AD - Hematology Department, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. FAU - Donsante, Samantha AU - Donsante S AD - Department of Molecular Medicine, Sapienza University, Rome, Italy. FAU - Di Marzo, Noemi AU - Di Marzo N AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Mottadelli, Federica AU - Mottadelli F AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Cardinale, Lucia AU - Cardinale L AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Dander, Erica AU - Dander E AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Isimbaldi, Giuseppe AU - Isimbaldi G AD - Department of Pathology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. AD - Department of Pathology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. FAU - Pioltelli, Pietro AU - Pioltelli P AD - Department of Hematology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. FAU - Biondi, Andrea AU - Biondi A AD - Department of Pediatrics, Fondazione MBBM/San Gerardo Hospital, Monza, Italy. FAU - Riminucci, Mara AU - Riminucci M AD - Department of Molecular Medicine, Sapienza University, Rome, Italy. FAU - D'Amico, Giovanna AU - D'Amico G AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Elli, Elena Maria AU - Elli EM AD - Department of Hematology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. elena.elli@libero.it. FAU - Pievani, Alice AU - Pievani A AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. FAU - Serafini, Marta AU - Serafini M AUID- ORCID: 0000-0001-8105-6476 AD - Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy. serafinim72@gmail.com. LA - eng GR - 211147/AIRC-5x1000 2018/ PT - Journal Article DEP - 20201021 PL - Germany TA - Ann Hematol JT - Annals of hematology JID - 9107334 RN - 0 (activin A) RN - 104625-48-1 (Activins) SB - IM MH - Activins/*metabolism MH - Adult MH - Aged MH - Bone Marrow/*metabolism/pathology MH - Cell Differentiation/physiology MH - Cells, Cultured MH - Cohort Studies MH - Female MH - Humans MH - Male MH - Mesenchymal Stem Cells/*metabolism/pathology MH - Middle Aged MH - Myeloproliferative Disorders/*metabolism/pathology MH - Polycythemia Vera/metabolism/pathology MH - Primary Myelofibrosis/*metabolism/pathology MH - Thrombocythemia, Essential/metabolism/pathology OTO - NOTNLM OT - ActivinA OT - Mesenchymal stromal cells OT - Myelofibrosis OT - Myeloproliferative neoplasms EDAT- 2020/10/23 06:00 MHDA- 2021/01/14 06:00 CRDT- 2020/10/22 05:41 PHST- 2020/05/25 00:00 [received] PHST- 2020/10/15 00:00 [accepted] PHST- 2020/10/23 06:00 [pubmed] PHST- 2021/01/14 06:00 [medline] PHST- 2020/10/22 05:41 [entrez] AID - 10.1007/s00277-020-04306-w [pii] AID - 10.1007/s00277-020-04306-w [doi] PST - ppublish SO - Ann Hematol. 2021 Jan;100(1):105-116. doi: 10.1007/s00277-020-04306-w. Epub 2020 Oct 21.