High frequency of clonal hematopoiesis in Erdheim-Chester disease

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.

Graphical abstract

Figure 1.

Clonal hematopoiesis in ECD. (A) Mutations (%) on each of the genes of the myeloid panel (BM samples), among patients with clonal hematopoiesis (n = 51). (B) Correlation between the number of mutated genes (y-axis, left) and total number of mutations (y-axis, right) and age at BM aspirate (x-axis). (C) Dendrogram plot of mutations in 51 patients.

Figure 2.

VAF of mutated genes. Box shows median, 25th, and 75th percentiles. Whiskers show minimal to maximal values. BM samples were used for genotyping. The full list of mutations with VAF is provided in supplemental Table 6.

Figure 3.

Mutational status of single-cell colonies derived from CD34⁺ 38⁻BM progenitor cells in 7 ECD patients. Mutational status of single-cell colonies derived from CD34⁺38⁻ progenitor cells of 3 ECD patients (#A, B/13, and C) harboring both MAPK pathway and additional myeloid mutations, and of 5 ECD patients (#D/7, E, F/4, G/16, and H) harboring myeloid mutations. Of note, a larger number of colonies were sequenced for the MAPK pathway mutations and only the colonies sequenced for both MAPK pathway mutations and additional myeloid mutations are depicted. Patients who had hematological neoplasms are indicated by “/X”, the X number referring to the number on Table 3. The full details of the mutation list, and correspondence between BM and tissue mutations, are shown in supplemental Table 7.