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Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Back to biology: new insights on inheritance in myeloproliferative disorders
Evan M Braunstein1, Alison R Moliterno
1Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, 720 Rutland Ave., Ross Research Building Room 1025, Baltimore, MD, 21205, USA, ebrauns3@jhmi.edu.
Abstract:
The myeloproliferative disorders (MPDs) are a group of hematologic diseases with significant overlap in both clinical phenotype and genetic etiology. While most often caused by acquired somatic mutations in hematopoietic stem cells, the presence of familial clustering in MPD cases suggests that inheritance is an important factor in the etiology of this disease. Though far less common than sporadic disease, inherited MPDs can be clinically indistinguishable from sporadic disease. Recently, germline mutations in Janus kinase 2 (JAK2) and MPL, two genes frequently mutated in sporadic MPD, have been shown to cause inherited thrombocytosis. Study of the function of these mutant proteins has led to a new understanding of the biological mechanisms that produce myeloproliferative disease. In this review, we summarize the data regarding inherited mutations that cause or predispose to MPDs, with a focus on the biological effects of mutant proteins. We propose that defining inherited MPDs in this manner has the potential to simplify diagnosis in a group of disorders that can be difficult to differentiate clinically.
Insights
Inherited mutations in JAK2 and MPL genes cause myeloproliferative disorders (MPDs), often presenting like sporadic forms. Understanding these inherited MPDs can simplify diagnosis.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Myeloproliferative disorders (MPDs) are hematologic diseases with overlapping clinical and genetic features.
- While often caused by acquired mutations, familial clustering suggests a role for inherited factors.
- Inherited MPDs can be clinically similar to sporadic forms, posing diagnostic challenges.
Purpose of the Study:
- To review inherited mutations predisposing to MPDs.
- To focus on the biological effects of these mutant proteins.
- To propose a diagnostic framework for inherited MPDs.
Main Methods:
- Literature review of inherited mutations in MPDs.
- Analysis of functional data for mutant JAK2 and MPL proteins.
- Synthesis of current understanding of MPD pathogenesis.
Main Results:
- Germline mutations in Janus kinase 2 (JAK2) and MPL cause inherited thrombocytosis.
- Study of these mutations reveals insights into MPD biological mechanisms.
- Inherited MPDs share genetic underpinnings with sporadic MPDs.
Conclusions:
- Defining inherited MPDs based on germline mutations can aid diagnosis.
- Understanding genetic etiology clarifies MPD pathogenesis.
- This approach may simplify the differentiation of MPD subtypes.
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