High frequency of clonal hematopoiesis in Erdheim-Chester disease

• DOI: 10.1182/blood.2020005101
• Publication Date: 2020-10-17T02:01:47Z
• Authors: Fleur Cohen Aubart; Damien Roos-Weil; Marine Armand; Alice Marceau-Renaut; Jean-François Emile; Nicolas Duployez; Frédéric Charlotte; Stéphanie Poulain; Raphael Lhote; Zofia Hélias-Rodz...; Véronique Della-V...; Olivier Bernard; Karim Maloum; Florence Nguyen-Khac; Jean Donadieu; Zahir Amoura; Omar Abdel-Wahab; Julien Haroche
• Keywords: Adult; Male; Erdheim-Chester Disease; Age Factors; Abnormal Karyotype; Exons; Middle Aged; Dioxygenases; 3. Good health; DNA-Binding Proteins; Cell Transformation, Neoplastic; Bone Marrow; Leukemia, Myeloid; Mutation; Disease Progression; Humans; Female; Clonal Hematopoiesis; Multiple Myeloma; Aged; Genes, Neoplasm

Abstract 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.