Inheritance of the chronic myeloproliferative neoplasms. A systematic review

Abstract

This systematic review investigated the inheritance of the classical chronic myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia (CML). Sixty-one articles were included and provided 135 families with a total of 341 participants distributed to various subtypes of MPN: 50% PV, 23% ET, 14% PMF, 10% CML and 3% non-MPN hematological disorder. Women developed the disease earlier than men (43.1 years vs 47.3 years; p = 0.074), while the general average age of onset was 46 years, notably younger than sporadic cases. The clinical phenotype of the families showed a homogenous (67%) and a heterogeneous (33%) pattern, with the majority being PV-PV pairs (36%) and PV-PMF pairs (17%), respectively. This observation suggests that the susceptibility gene (or genes) is not restricted to one subtype supporting the hypothesis of a mutation in an early multipotent stem cell. Furthermore, a major subgroup of families provided evidence of an autosomal dominant (AD) inheritance with reduced penetrance. This study suggests that the origin of MPNs may occur in at least three different settings: (i) a sporadic, (ii) genetic heterogeneity with polygenetic and environmental impact and (iii) a familial phenotype following an AD inheritance.

Myeloproliferative Neoplasms in Danish Twins

“…Although this result is not statistically significant, it is in accordance with 2 larger MPN studies [15, 16]. Future studies could focus on families with multiple affected members, which would shed further light on the heritability of MPNs [2, 7, 9, 17]. …”

“…According to the WHO classification, the classical Philadelphia-negative MPNs – essential thrombocythemia, polycythemia vera, and primary myelofibrosis – are classified along with chronic myelogenous leukemia (CML) [1]. Although the etiology is largely unknown, case reports, including 4 case reports with concordant monozygotic (MZ) twin pairs, have suggested a familial aggregation of MPNs, supporting the concept of a genetic component to MPN [2-6]. …”

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib

“…24 It is suggested that the 'familial MPN susceptibility gene' might exist in a multipotent stem cell and that the familial clustering of MPN is associated with a genetic heterogeneity, multifactorial inheritance or autosomal dominant inheritance with variable penetrance. 25 In conclusion, treatment with the JAK1 and JAK2 inhibitor ruxolitinib and allogeneic HCT are not mutually exclusive. Through the reduction of proinflammatory and proangiogenic cytokines, some of the patient-related negative predictors for outcome after allogeneic HCT such as poor PS and massive splenomegaly might be, at least partly, counteracted.…”

Haemoglobinopathia Ypsilanti – A rare, but important differential diagnosis to polycythaemia vera

“…The inheritance in myeloproliferative disorders is complex and difficult to evaluate in a single family (Fig. 1) [7]. Hereditary erythrocytosis can be associated with mutations in the gene encoding the erythropoietin receptor, defects in the oxygen sensing pathways and abnormal oxygen delivery [8].…”