Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis
| Autor: | Xin Lei, Paul Geraeds Kemps, Tom de Wit, Jelske Borst, Yanling Xiao, Jannie Borst, Rhianne Voogd, Joanna Grabowska, Eline C. Steenwijk, Astrid G. S. van Halteren, Cor van den Bos, Jennifer Picarsic |
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| Přispěvatelé: | CCA - Cancer biology and immunology |
| Rok vydání: | 2020 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Myeloid Langerhans cell Immunology Population CD34 Biology Biochemistry Langerhans cell histiocytosis Bone Marrow medicine Humans Progenitor cell education Myeloid Progenitor Cells Progenitor education.field_of_study Cell Differentiation Cell Biology Hematology Dendritic Cells medicine.disease Histiocytosis Langerhans-Cell medicine.anatomical_structure Mutation Cancer research Bone marrow |
| Zdroj: | Blood, 136(19), 2188-2199. American Society of Hematology Blood, 136(19), 2188-2199. AMER SOC HEMATOLOGY Xiao, Y, van Halteren, A G S, Lei, X, Borst, J, Steenwijk, E, de Wit, T, Grabowska, J, Voogd, R, Kemps, P, Picarsic, J, van den Bos, C & Borst, J 2020, ' Bone marrow-derived myeloid progenitors as driver mutation carriers in high-and low-risk Langerhans cell histiocytosis ', Blood, vol. 136, no. 19, pp. 2188-2199 . https://doi.org/10.1182/blood.2020005209 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2020005209 |
| Popis: | Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ–positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO− and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo’s)/macrophages (MΦs), osteoclasts (OCs), and DCs. CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo’s /MΦs, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood. |
| Databáze: | OpenAIRE |
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