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Advances in the molecular pathology of MDS

PubMed Abstract: 
Original Publication Date: 
Thursday, November 19, 2015

Stephanie Halene, M.D.
Assistant Professor
Section of Hematology/Department of Internal Medicine and Yale Cancer Center


Kai Rejeski, Visiting Medical Student, Freiburg University
Yale University School of Medicine

Molecular pathology of myelodysplastic syndromes: new developments and implications for diagnosis and treatment.
Zhang X, Lancet JE, Zhang L.
Leuk Lymphoma. 2015 May 26:1-9. [Epub ahead of print]

Current and novel therapeutic approaches in myelodysplastic syndromes.
Estephan F, Tiu RV.
J Community Support Oncol. 2014 Jul;12(7):236-249. doi: 10.12788/jcso.0057. Review.
PMID: 25830232 [PubMed - as supplied by publisher]

In these reviews, Zhang, Lancet, and Zhang, and Estephan and Tiu highlight the advent of genomic sequencing and how it has changed our understanding of the mechanisms leading to myelodysplasia. Prior to next generation sequencing, only gross chromosomal abnormalities were evident in MDS. Now we can identify abnormalities at the molecular level and predict and test loss or gain of function of individual proteins. This has not only led to the identification of novel molecular markers implicated in MDS, but has also greatly advanced our understanding of how MDS happens.

While gene mutations are helpful during diagnosis, mutations truly specific for MDS have not been identified. The mutational spectrum highlights the commonalities between MDS and other myeloid as well as lymphoid malignancies. Commonly mutated genes include those of DNA methylation, histone modification, signal transduction, transcription factors, RNA Splicing and Tyrosine Kinases. The authors surmise that while the new molecular insights are promising, it remains a challenge to integrate these complex findings into prevailing clinical prognostication systems and clinical practice. The frequent finding of more than one mutation in patients confirms that MDS are a group of heterogeneous disorders and that one treatment does not fit all. On the contrary – a single agent, other than replacement of the bone marrow with stem cells from a healthy matched donor, is unlikely to achieve cure as patients carry mutations in genes affecting multiple pathways that may also evolve in response to treatment. These challenges, however, also offer opportunity. With more and more extensive knowledge about the makeup of each patient’s MDS and the advent of “targeted” therapies directed at individual mutations and pathways, personalized therapies - including single agents and combination therapies - are the focus of intensive research and clinical trials.

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