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Published on: February 21, 2018
The Molecular Genetics of Myeloproliferative Neoplasms
Anna E Marneth1, Ann Mullally1,2,3
1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Activated JAK-STAT signaling is central to the pathogenesis of BCR-ABL-negative myeloproliferative neoplasms (MPNs) and occurs as a result of MPN phenotypic driver mutations in JAK2, CALR, or MPL The spectrum of concomitant somatic mutations in other genes has now largely been defined in MPNs. With the integration of targeted next-generation sequencing (NGS) panels into clinical practice, the clinical significance of concomitant mutations in MPNs has become clearer. In this review, we describe the consequences of concomitant mutations in the most frequently mutated classes of genes in MPNs: (1) DNA methylation pathways, (2) chromatin modification, (3) RNA splicing, (4) signaling pathways, (5) transcription factors, and (6) DNA damage response/stress signaling. The increased use of molecular genetics for early risk stratification of patients brings the possibility of earlier intervention to prevent disease progression in MPNs. However, additional studies are required to decipher underlying molecular mechanisms and effectively target them.
Insights
Concomitant mutations in myeloproliferative neoplasms (MPNs) impact disease progression. Understanding these genetic alterations aids in early risk stratification and potential interventions for MPNs.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Activated Janus kinase-Signal transducer and activator of transcription (JAK-STAT) signaling drives myeloproliferative neoplasms (MPNs).
- Driver mutations in JAK2, CALR, or MPL are key in MPN pathogenesis.
- The landscape of co-occurring somatic mutations in MPNs is increasingly understood.
Purpose of the Study:
- To review the clinical significance of concomitant mutations in MPNs.
- To elucidate the consequences of mutations in frequently altered gene classes within MPNs.
Main Methods:
- Review of current literature on concomitant mutations in MPNs.
- Analysis of data from targeted next-generation sequencing (NGS) panels.
- Categorization of mutations by affected pathways: DNA methylation, chromatin modification, RNA splicing, signaling, transcription factors, and DNA damage response.
Main Results:
- Concomitant mutations affect multiple cellular pathways critical to MPN development.
- Next-generation sequencing (NGS) integration clarifies the clinical impact of these mutations.
- Specific mutation classes reviewed include DNA methylation, chromatin, splicing, signaling, transcription factors, and DNA damage response.
Conclusions:
- Understanding concomitant mutations is crucial for risk stratification in MPNs.
- Molecular genetics enables earlier detection and intervention strategies.
- Further research is needed to fully elucidate mechanisms and develop targeted therapies for MPNs.
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