Elsevier

Leukemia Research

Volume 39, Issue 1, January 2015, Pages 6-17
Leukemia Research

Review Article
The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes

https://doi.org/10.1016/j.leukres.2014.10.006Get rights and content

Highlights

  • Gene mutation status has been implicated in diagnosis of MDS and risk stratification.

  • Gene mutations play key roles in pathogenesis and progression of MDS.

  • Interrogating the genetics of MDS may facilitate development of targeted therapeutics.

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous cluster of clonal hematopoietic neoplasms manifested by peripheral cytopenias, lineage dysplasia, and a predisposition to acute myeloid leukemia. The pathophysiology of MDS has not been well illustrated. Nevertheless, studies have implicated the MDS phenotype in a broad spectrum of genetic abnormalities. In addition to the known numerical and structural chromosomal abnormalities, with novel genomic sequencing technologies, approximately 80% of MDS patients have been shown to harbor somatic or acquired gene mutations. The mutations have been found to be related to RNA slicing, transcription regulation, DNA methylation, histone modification, DNA repair/tumor suppressor, signal transduction, and the cohesion complex. The clinical significance of the majority of genetic events has been validated based on a large cohort study that identified mutations as predictors for risk stratification in MDS patients and biomarkers for potential targeted therapies. In this review, we describe all novel key mutations in MDS and their significance in pathophysiology and clinical practice.

Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by peripheral cytopenia, bone marrow dyspoiesis with or without excess blasts, and >30% transformation rate to acute myeloid leukemia (AML) [1]. The disease poses a unique diagnostic challenge for both hematologists and pathologists because of its clinicopathologic diversity and its benign or malignant mimickers. Although the current evaluation of a suspected MDS includes clinical history, peripheral blood value, bone marrow morphology and architecture, flow cytometry, and cytogenetics study, many cases of true MDS remain diagnostically challenging. Preclinical studies have clearly shown that the development of MDS is derived from acquired genetic mutations independent of their phenotypic or morphologic presentation [2], [3]. Further evidence also supports that a wide spectrum of genetic aberrations has been implicated in the prognosis and behavior of individual MDS cases [3]. Several informative clinical prognostic tools exist for the risk stratification of MDS, but it has become apparent that incorporation of genetic mutations may further enhance the efficacy of current clinical tools [4], [5].

Most patients with MDS have a detectable gene mutation, making its clinical implementation broadly applicable. According to recent large cohort studies of MDS patients, 72–90% of cases carried at least one mutation (average of 3/per case) [6], [7], [8]. Currently, various driver mutations identified in MDS represent genes involved in pathways important in epigenetic regulation, including chromatin modification and DNA methylation, transcriptional regulation, DNA repair/tumor suppressor, signal transduction, RNA splicing machinery, and the cohesion complex (Table 1). Although over 60 genes have been recently identified, there are 6 genes (TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1) that are consistently mutated in 10% or more of MDS patients [6], [7], [9]. Herein, we review the clinical and pathological significance of these mutations as grouped by corresponding pathways that they dysregulate.

Section snippets

DNA methylation

Epigenetic pathways are involved in manipulation of the level of DNA methylation and the modification of DNA or its protein interactions, including methylation, acetylation, and phosphorylation of histone residues of nucleosomes around which the DNA double helix winds [10], [11]. Of note, DNA methylation and direct DNA and DNA-associated histone modification represent critical mechanisms of altered epigenetic regulation in MDS (Fig. 1). Abnormalities in cytosine methylation may result from

Chromatin/histone modification

ASXL1, EZH2, and UTX are members of pathways that control histone post-translational modifications. Mutations in ASXL1, EZH2, and UTX have been identified in MDS and appear to alter histone biology, resulting in dysregulation of gene expression in MDS [20].

RUNX1

The RUNX proteins are critical regulators of myeloid differentiation in all vertebrates. Germline point mutations of RUNX1 (runt-related transcription factor 1) were first described in familial platelet disorders evolving to AML [79]. The mutation was also subsequently reported in MDS [80], [81] and CMML [82]. RUNX1 mutations have been found at a much higher frequency (23.6%) in patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and AML following MDS

TP53

TP53 is a tumor suppressor gene with a critical role in both cell cycle regulation and DNA repair. The gene encoded tumor protein TP53 binds directly to DNA and determines whether the damaged DNA undergoes repair and apoptosis. TP53 mutations are ubiquitously mutated in human cancers and have been clearly identified to be oncogenic [117]. An early study showed detected missense point mutations of p53 have been detected in 3 of 44 patients with high-grade MDS (2 RAEB and 1 RAEB-T/AML) [118]. A

JAK2

JAK2 (Janus kinase 2), located at 9p24, belongs to the Janus kinase family and is the sentinel kinase in many hematopoietic signaling cascades. A missense mutation within the pseudokinase domain of JAK2 (a change of valine to phenylalanine at the 617 position) causes constitutional activation of the tyrosine kinase in the absence of ligand stimulation (e.g., interferon, GM-CSF, erythropoietin, and thrombopoietin). JAK2 mutation has been identified in BCR-ABL-negative myeloproliferative

RNA splicing

RNA splicing is a necessary process such that pre-messenger RNA (pre-mRNA) transcripts are processed so that introns are removed and exons are joined to form mature RNA. The core proteins responsible for this pathway form the spliceosome complex (Fig. 2). Mutations have been identified in myeloid malignancies and have been demonstrated to dysregulate RNA splicing [6] (Fig. 2).

Mutations of RNA-splicing genes are the most frequently observed mutations in MDS, occurring in up to 50% of cases, the

The cohesin complex

The cohesin complex includes SMC1, SMC3, SCC1/RAD21, SCC3/STAG, WPL1, and PDS5B. These genes are located at disparate chromosomal locus but act together in control of cell division (centrosomes, hetrochromatin, DNA duplication, gene expression, and chromosome segregation) through regulating dissociation of sister chromatids in mitosis or meiosis [152] (Fig. 3).

Mutations in the cohesin gene family members (mainly STAG1, STAG2, SMC3, SMC1A, PDS5B, and RAD21) have been recently reported in myeloid

Summary

An explosion in the discovery and understanding of novel mutations in MDS has provided an important pathophysiologic and prognostic insight into this extraordinarily heterogeneous disease. In addition, the discovery of these mutations, particularly if pathogenic or initiating, will provide important avenues for exploring novel therapeutic approaches toward modulating their effectors’ activity. It is hoped and expected that prospective therapeutic trials will be launched in the coming months to

Conflict of interest statement

None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

Acknowledgements

All authors disclose no any financial or personal relationships with the other organizations that could inappropriately influence the works.

Contributors. L. Zhang (LZ) and E. Padron (EP) contributed equally. LZ and EP have made substantial contributions to the study design and construction, acquisition and analysis of data and draft the manuscript. JE Lancet (JEL) have reviewed and modified the manuscript. All authors have a final approval of the version. We thank Rasa Hamilton (Moffitt Cancer

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