Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019621 (Langerhans cell histiocytosis)
3,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34⁺ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34⁺ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34⁺ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm.
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PMID:Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. 2856 92

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a⁺CD207⁺ LCH cells. In LCH, somatic mutations of the BRAF ^V600E gene have been detected in tissue LCH cells, bone marrow CD34⁺ hematopoietic stem cells, circulating CD14⁺ monocytes, and BDCA1⁺ myeloid dendritic cells (DC). Targeting BRAF ^V600E in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1a⁺CD207⁺ LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14⁺ monocytes, BDCA1⁺ DCs, and CD34⁺ cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAF ^V600E cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAF ^V600E and wild-type forms of the disease.
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PMID:CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis. 3223 82


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