X chromosome inactivation analysis reveals a difference in the biology of ET patients with JAK2 and CALR mutations

Abstract

AbstractCalreticulin mutations (CALRMUT) are found in a significant proportion of patients with essential thrombocythemia (ET) lacking JAK2V617F or MPL mutations. They are associated with substantially different hematological and clinical features and define a distinct subtype of ET. We show here that their presence is significantly correlated with a clonal X chromosome inactivation pattern (XCIP). Of 105 female ET patients investigated, 61 had an interpretable XCIP, and a clonal pattern was observed in 88% of CALRMUT patients compared with 26% of JAK2V617F (P = .0002) and 9% of JAK2V617F/MPL/CALR wild-type patients (P < .0001). Neutrophil CALRMUT level was significantly higher than JAK2V617F level (median, 50% vs 18%; P < .0001), and wild-type myelopoiesis was suppressed in CALRMUT but not JAK2V617F patients. These data are suggestive of truly monoclonal hematopoiesis in CALRMUT patients and provide further evidence that the biology associated with CALR mutations is markedly different from that of JAK2V617F mutations.