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Blood. 2017 Jul 13;130(2):176-180. doi: 10.1182/blood-2016-12-757377. Epub 2017 May 31.

Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells.

Author information

1
Department of Pathology and.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
3
Unité Mixte de Recherche (UMR)1170, INSERM and Institut Gustave Roussy, Villejuif, France.
4
Sorbonne Universités, UPMC/Paris 06, UMR-S INSERM U1135, Centre National de la Recherche (CNRS) ERL 8255, Centre d'Immunologie et Maladies Infectieuses, Paris, France.
5
Assistance Publique-Hôpitaux de Paris (AP-HP), University Hospital La Pitié-Salpêtrière, Department of Internal Medicine, Centre de Référence des Histiocytoses, Paris, France.
6
Department of Immunology, AP-HP Pitié Salpêtrière, Paris, France.
7
EA4340, Versailles University, Paris-Saclay University, Boulogne, France.
8
Pathology Service, Hôpital Universitaire Ambroise Paré, AP-HP, Boulogne, France.
9
Leukemia Service, Department of Medicine, and.
10
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY.
11
Department of Pathology, New York University School of Medicine, New York, NY.
12
Department of Internal Medicine, AP-HP, University Hospital Bichat, Paris, France.
13
Department of Pathology, University Hospital La Pitié-Salpêtrière, Paris, France; and.
14
INSERM UMR-S1147, CNRS SNC5014, Paris Descartes University, Paris, France.

Abstract

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.

PMID:
28566492
PMCID:
PMC5510787
DOI:
10.1182/blood-2016-12-757377
[Indexed for MEDLINE]
Free PMC Article

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