High frequency of clonal hematopoiesis in Erdheim-Chester disease

• Published in: Blood 2021-01, Vol.137 (4), p.485-492
• Main Authors: Cohen Aubart, Fleur, Roos-Weil, Damien, Armand, Marine, Marceau-Renaut, Alice, Emile, Jean-François, Duployez, Nicolas, Charlotte, Frédéric, Poulain, Stéphanie, Lhote, Raphael, Hélias-Rodzewicz, Zofia, Della-Valle, Véronique, Bernard, Olivier, Maloum, Karim, Nguyen-Khac, Florence, Donadieu, Jean, Amoura, Zahir, Abdel-Wahab, Omar, Haroche, Julien
• Format: Article
• Language: English
• Subjects: Abnormal Karyotype; Adult; Age Factors; Aged; Bone Marrow - pathology; Cell Transformation, Neoplastic - genetics; Clonal Hematopoiesis - genetics; Dioxygenases; Disease Progression; DNA-Binding Proteins - genetics; Erdheim-Chester Disease - genetics; Erdheim-Chester Disease - physiopathology; Exons - genetics; Female; Genes, Neoplasm; Hematopoiesis and Stem Cells; Humans; Immunology; Leukemia, Myeloid - genetics; Life Sciences; Male; Middle Aged; Multiple Myeloma - genetics; Mutation; Myelodysplastic Syndromes - genetics; Neoplasm Proteins - genetics; Neoplastic Stem Cells - pathology; Organ Specificity; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020005101

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38− BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD. •ECD patients have a very high frequency of clonal hematopoiesis and concomitant overt myeloid malignancies.•ECD patients with clonal hematopoiesis are older and have more frequent retroperitoneal involvement and BRAFV600E mutations. [Display omitted]