Various hypothetical scenarios depicting the interplay between CH (especially TET2) and MAPK-ERK mutations, and its role in the pathogenesis of ECD and concomitant myeloid neoplasms. Sequential acquisition of driver mutations can occur due to pressure from bone marrow microenvironment, leading to development of myeloid neoplasms and ECD (scenario 1). There may be unknown alterations in the progenitor cells that lead to development of ECD and myeloid neoplasm (scenario 2). In various scenarios, TET2-mutant cells can lead to selective growth of MAPK-ERK–mutated histiocytes in a paracrine manner. Alternately, MAPK-ERK–mutant myeloid cells can also stimulate TET2 mutations. In the most common scenarios (3 and 4), however, ECD occurs without myeloid neoplasms irrespective of the presence of CH.