Genetic–pathologic characterization of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic–pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome. Three distinct “driver“ mutations were found in over 80% of cases of specific forms of uncontrolled growth in stem cells making blood cells. Driver mutations are directly responsible for the harmful cell multiplication, unlike neutral mutations that are found in affected cells but do not cause the disease. Myungshin Kim and co-workers at The Catholic University of Korea identified the mutations in 407 patients with bone marrow disorders leading to uncontrolled multiplication of blood cells. Their evidence suggests each mutation is sufficient to drive disease progression on its own, although two of the mutations occurred together in cells from one patient. The research corroborated some existing proposals about the development of these disorders and also offered new insights into their pathogenesis and progression. The findings may guide new approaches to treatment.