Gene Mutations In Myelodysplastic Syndromes Research Articles

Advances in the application of Raman spectroscopy in haematological tumours.

Hematologic malignancies are a diverse collection of cancers that affect the blood, bone marrow, and organs. They have a very unpredictable prognosis and recur after treatment. Leukemia, lymphoma, and myeloma are the most prevalent symptoms. Despite advancements in chemotherapy and supportive care, the incidence rate and mortality of patients with hematological malignancies remain high. Additionally, there are issues with the clinical diagnosis because several hematological malignancies lack defined, systematic diagnostic criteria. This work provided an overview of the fundamentals, benefits, and limitations of Raman spectroscopy and its use in hematological cancers. The alterations of trace substances can be recognized using Raman spectroscopy. High sensitivity, non-destructive, quick, real-time, and other attributes define it. Clinicians must promptly identify disorders and keep track of analytes in biological fluids. For instance, surface-enhanced Raman spectroscopy is employed in diagnosing gene mutations in myelodysplastic syndromes due to its high sensitivity and multiple detection benefits. Serum indicators for multiple myeloma have been routinely used for detection. The simultaneous observation of DNA strand modifications and the production of new molecular bonds by tip-enhanced Raman spectroscopy is of tremendous significance for diagnosing lymphoma and multiple myeloma with unidentified diagnostic criteria.

Distinct genetic landscapes and their clinical implications in younger and older patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of clinically and genetically diverse diseases that impose patients with an increased risk of leukemic transformation. While MDS is a disease of the elderly, the interplay between aging and molecular profiles is not fully understood, especially in the Asian population. Thus, we compared the genetic landscape between younger and older patients in a cohort of 698 patients with primary MDS to advance our understanding of the distinct pathogenesis and different survival impacts of gene mutations in MDS according to age. We found that the average mutation number was higher in the older patients than younger ones. The younger patients had more WT1 and CBL mutations, but less mutated ASXL1, DNMT3A, TET2, SF3B1, SRSF2, STAG2, and TP53 than the older patients. In multivariable survival analysis, RUNX1 mutations with higher variant allele frequency (VAF) and U2AF1 and TP53 mutations were independent poor prognostic indicators in the younger patients, whereas DNMT3A and IDH2 mutations with higher VAF and TP53 mutations conferred inferior outcomes in the older patients. In conclusion, we demonstrated the distinct genetic landscape between younger and older patients with MDS and suggested that mutations impact survival in an age-depended manner.

Synthetic Data Generation By Artificial Intelligence to Accelerate Translational Research and Precision Medicine in Hematological Malignancies

Background In hematological malignancies there is a growing demand for real-world, comprehensive data including clinical and genomic information to build powerful models to improve diagnosis, prognosis and personalized treatment choice. However, collecting such information in large patient populations is challenging and there are many issues concerning patient privacy that need to be accounted for. One approach that can circumvent these issues is the creation of synthetic data that captures the complexities of the original data set (distributions, non-linear relationships, and noise) without including any real patient information. Aims 1) Apply advanced synthetic data generation methods to real-world datasets of different hematological malignancies. 2) Develop a Synthetic Validation Framework to evaluate the quality of synthetic data and perform data augmentation. 3) Test the capability of synthetic data to accelerate translational research. Methods Here we implemented a Conditional Tabular Wasserstein Generative Adversarial Networks (GAN) architecture with Gradient Penalty to generate synthetic data. Use cases were different cohorts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with available clinical and molecular features. We created a Synthetic Validation Framework to evaluate the quality of generated synthetic data: Clinical Synthetic Fitness (CSF) and Genomic Synthetic Fitness (GSF) scores were calculated as the average of multiple metric tests adopted. Patients were stratified by Hierarchical Dirichlet (HD) clustering. Explainability analysis was carried out by SHapley Additive exPlanations approach (SHAP). Survival analyses were performed by Kaplan-Meier curves and CoxPH models (Experimental plan is reported in Figure 1). Results We first created a synthetic copy of a MDS cohort (n=2,043) using all the real data for training the model. We compared synthetic vs. real data, obtaining high fitness performances for both clinical and genomic features (CSF=93%; GSF=90%). HD were then applied to define clusters capturing broad dependencies among genomic features, showing comparable results in synthetic vs. real data; SHAP analysis indicated that similar features drive patients’ classification in both datasets. Finally, synthetic patients had comparable survival with respect to real ones; when applying conventional scoring system (IPSS-R), the probability of survival of the 5 risk categories was comparable between synthetic and real data. In the second experiment setting, we analysed synthetic MDS datasets with different size generated with model trained on a real dataset. Interestingly, when generating a synthetic augmented dataset (200%) we obtained high fitness performance for both clinical and genomic features (CSF=91%; GSF=89%). Moreover, all the performances showed a similar trend when considering a cohort of 1,002 patients with AML (CSF=92%; GSF=89%) thus proving evidence for high generalizability of the model across different clinical settings. Finally, we investigated if the generation of synthetic data can accelerate translational research in hematology. Since the first publication on clinical relevance of gene mutations in MDS (Leukemia 2014;28:241), it took several years to collect data in large patient populations for generating a molecular classification (JCO 2021;39:1223) and prognostic score (IPSS-M, NEJM Evid 2022;1:7). Starting from the MDS cohort available in 2014 (n=944, Leukemia 2014;28:241), we generated 300% augmented synthetic dataset. HD were applied to synthetic data to define genomic-based clinical entities, resulting in the identification of the same 8 subgroups described in a real cohort of 2,043 patients many years later. Moreover, we applied a CoxPH model to the synthetic dataset to generate a molecular prognostic score (IPSS-M_Syn). The model was based on similar molecular features as the real IPSS-M and identified 6 risk categories in which the probability of survival was similar to that of IPSS-M risk groups (Figure 2). Conclusion GAN-generated synthetic data recapitulate statistical properties and complexity of clinical and genomic features in different hematological malignancies, replicate reliable survival estimates and allow effective data augmentation. The implementation of this technology seems to accelerate precision medicine research in hematology. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictive and prognostic value of gene mutations in myelodysplastic syndrome treated with hypomethylating agents: a meta-analysis

Although the effect of gene mutations on overall response rate (ORR) and overall survival (OS) in myelodysplastic syndrome (MDS) treated with hypomethylating agents (HMAs) has been explored, the effect is still controversial. We performed this meta-analysis to investigate the effect. The pooled odds ratio (OR) and 95% confidence interval (CI) for ORR and the pooled hazard ratio (HR) and 95%CI for OS were chosen to estimate the effect. The pooled OR of TET2 was 0.73 (95%CI: 0.59–0.91, p = 0.005) and the pooled OR of ASXL1 was 1.38 (95%CI: 1.12–1.71, p = 0.003). As for prognosis, the pooled HR of RUNX1 was 1.45 (95%CI: 1.15–1.85, p = 0.002). The pooled HR of TP53 was 2.30 (95%CI: 1.83–2.90, p < 0.001) and the pooled HR of U2AF1 was 1.41 (95%CI: 1.15–1.74, p = 0.001). There was no statistical difference shown in other genes. Therefore, TET2 mutation and ASXL1 wild-type were the predictor of better response to HMAs. Mutations of TP53, RUNX1, and U2AF1 were associated with poor prognosis in MDS.

Comparison of myeloid blast counts and variant allele frequencies of gene mutations in myelodysplastic syndrome with excess blasts and secondary acute myeloid leukemia

Secondary acute myeloid leukemia (sAML) is biologically and clinically distinct from de novo AML and shares specific genetic mutations with myelodysplastic syndromes (MDS). We retrospectively analyzed data from 295 adults with MDS or AML with mutational analysis by next-generation sequencing (NGS), and examined differences in functional grouping of mutations and relation between morphologic blast count and variant allele frequency (VAF) of mutations. Our analysis showed the distribution of mutations differed in MDS and AML. However, these differences largely disappeared when we compared MDS with excess blasts (MDS-EB) and sAML. VAF of mutations generally did not correlate with morphologic blast count and the distribution of VAF was similar above and below the 20% cutpoint. Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity therapy and survival was also similar. These results support that MDS-EB and sAML have overlapping features and may represent a spectrum of the same disease. Key points The distribution of genetic mutations is similar in myelodysplastic syndrome with excess blasts (MDS-EB) and secondary acute myeloid leukemia (sAML) regardless of morphologic blast count. Variant allele frequencies (VAFs) of gene mutations do not correlate well with morphologic blast counts, particularly in MDS-EB and sAML. Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity or low intensity therapy.

ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-Risk MDS: A Multicenter, Phase II Study

ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-Risk MDS: A Multicenter, Phase II Study

Research Progress on Role of Gene Mutations in Prognostic Evaluation of Patients with Myelodysplastic Syndrome after Stem-Cell Transplantation--Review

Abstract Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, high risk of transformation from MDS into AML. Allogeneic hematopoietic stem-cell transplantation is the only curative therapy for MDS, but the failure rate of transplantation is still high, which attribute to relapsed disease and transplant-related complications. Recently, the spectrum of gene abnormalities in MDS has been revealed by next generation genomic sequencing techniques. It was found that more than 80% MDS patients have at least one gene mutation. Mutated genes in MDS are powerfully associated with clinical phenotype and prognosis. In this review , the recent advancements regarding recurrent gene mutations in MDS are briefly summarized, and the prognostic values of gene mutations are discussed in MDS or after allogeneic hematopoietic stem-cell transplantation,so as to set up a predicting model and to guide the treatment.

Progression of gene mutations in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of heterogeneous and acquired clonal hematopoietic disorders diseases. In recent years, MDS-related gene mutations have become a research hotspot and important biological markers. The gene mutations of MDS varied. Among them, the gene mutation rate of RNA-splicing gene is the highest and gene mutation is related to the pathogenesis of MDS. SF3B1 mutation was first included in the diagnostic criteria by World Health Organization (WHO) in 2016 and the only good prognostic factor. Poor prognosis of gene mutations in the low-grade MDS may indicate the possibility of progression to high-grade MDS. The future of MDS treatment focuses target drugs. To further guide the clinical work, this article reviews the diversity of MDS-related mutations and its relationship with pathogenesis, diagnosis, treatment and prognosis. Key words: Myelodysplastic syndromes; Mutation; Diagnosis; Prognosis; Drug therapy

Advances in molecular genetics of myelodysplastic syndromes

In recent years, with the application of whole-genome sequencing technology, more and more gene mutations in myelodysplastic syndrome (MDS) have been studied and analyzed. Common gene mutations involve RNA splicing, DNA methylation, histone modification, transcription factor, adhesion protein complex, signal transduction pathway kinase, DNA repair and RAS signaling pathway and so on. More and more studies have confirmed that the gene mutations are associated with the unique clinical features of MDS and prognosis. For example, TP53 and arginine/serine rich splicing factor (SRSF)2 gene mutations are associated with the progression of MDS, MDS patients with TET2 mutations respond well to methylation drug treatment; and enhancer of zeste homolog (EZH)2, ETS variant gene (ETV)6, RUNX1 mutations associated with poor prognosis of MDS. This article reviews literatures on advances in molecular genetics of MDS. Key words: Myelodysplastic syndromes; Mutation; Diagnosis; Prognosis

Fanconi Anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML.

Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS.

Abstract IA11: Spliceosome gene mutations in MDS: Biology and potential therapeutic strategies

Abstract Somatic mutations in genes that are involved in pre-mRNA splicing (i.e., spliceosome genes) occur in ~50% of patients with myelodysplastic syndromes (MDS). Commonly mutated spliceosome genes (e.g., SF3B1, SRSF2, and U2AF1) have variable prognostic significance in patients with myeloid malignancies. For example, SRSF2 and U2AF1 mutations are associated with worse and SF3B1 mutations with better clinical outcomes compared to patients without a spliceosome gene mutation. While multiple groups have shown that RNA splicing is altered in patients with spliceosome gene mutations, the contribution of these alterations to disease pathogenesis is largely unknown. Several groups have reported that RNA splicing and hematopoiesis are altered in mutant-expressing mouse models, providing direct evidence that spliceosome gene mutations contribute to some MDS phenotypes. Spliceosome gene mutations have also been detected in the blood cells of healthy elderly individuals with clonal hematopoiesis who are at an increased risk of developing hematopoietic cancer, further implicating these mutations as early genetic drivers in MDS. Consistent with this possibility, spliceosome gene mutations tend to occur in the founding clone (i.e., present in every tumor cell in a patient) of myeloid malignancies. Collectively, these observations indicate that targeting mutant cells could have a large clinical impact. Several observations indicate that spliceosome gene mutations may create a genetic vulnerability in cells that could be exploited therapeutically. Spliceosome gene mutations are typically heterozygous and mutually exclusive of each other in patients, implying either a redundancy in pathogenic function of mutant genes or that a cell cannot tolerate two spliceosome perturbations at once. Accumulating evidence now suggests that heterozygous mutant cells require appropriate expression levels of the nonmutant residual allele or other splicing factors to maintain cell viability. Therefore, we and others hypothesize that cells harboring spliceosome mutations will have increased sensitivity to pharmacologic perturbation of the spliceosome, providing a new treatment approach for patients with these mutations. To examine this, we used sudemycin compounds that bind the SF3B1 protein to modulate pre-mRNA splicing. We show that treatment of U2AF1 mutant mice with sudemycin results in attenuation of mutant-associated hematopoietic progenitor cell expansion compared to control treated mice. Collectively, data from our group and others suggest that cells expressing mutant spliceosome genes have an increased sensitivity to pharmacologic perturbation of splicing. Clinical trials are being designed and conducted to treat spliceosome mutant hematologic cancers with splicing modulator compounds. Citation Format: Matthew J. Walter. Spliceosome gene mutations in MDS: Biology and potential therapeutic strategies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA11.

Role of Aberrant Splicing in Pathogenesis of Myelodysplastic Syndromes-Review

The spectrum of genetic abnormalities in myelodysplastic syndromes(MDS) has been revealed by high-throughput sequencing. However, the functional role of these mutations in occurrence and development of MDS was not delineated. The mutations in splicing factors have been identified as the commonest gene mutations in MDS. Recently, it was reported that the mutated or dysregulated splicing factors, including SF3B1, SRSF2 and U2AF1, attribute to aberrant mRNA splicing, which leads to hematopoietic dysfunction and drives MDS. These findings will be of great help in searching for candidate therapeutic targets in mis-splicing pathway in MDS. In this review the role of aberrant splicing in pathogenesis of MDS is summarized briefly.

Exploration of the role of gene mutations in myelodysplastic syndromes through a sequencing design involving a small number of target genes

Novel sequencing designs are necessary to supplement the recognized knowledge of myelodysplastic syndrome (MDS)-related genomic alterations. In this study, we sequenced 28 target genes in 320 Chinese MDS patients but obtained 77.2% of recall factors and 82.8% of genetic abnormalities (including karyotype abnormalities). In addition to known relationships among mutations, some specific chromosomal abnormalities were found to link to specific gene mutations. Trisomy 8 tended to be linked to U2AF1 and ZRSR2 mutations, and 20q- exhibited higher SRSF2/WT1 and U2AF1 mutation frequency. Chromosome 7 involvement accounted for up to 50% of RUNX1 mutations and 37.5% of SETBP1 mutations. Patients carrying a complex karyotype were prone to present TP53 mutations (36.1%). However, individuals with normal karyotypes rarely possessed mutations in the TP53, RUNX1 and U2AF1. Moreover, DNMT3A, TP53, SRSF2, STAG2, ROBO1/2 and WT1 predicted poor survival and high AML transformation. By integrating these predictors into international prognostic scoring system (IPSS) or revised IPSS, we built a set of mutation-based prognostic risk models. These models could layer different degrees of risk in patients more satisfactorily. In summary, this sequencing design was able to detect a number of gene mutations and could be used to stratify patients with varied prognostic risk.

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

AbstractDespite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.

Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts

Heterozygous somatic mutations affecting the spliceosome gene SF3B1 drive age-related clonal hematopoiesis, myelodysplastic syndromes (MDS) and other neoplasms. To study their role in such disorders, we generated knock-in mice with hematopoietic-specific expression of Sf3b1-K700E, the commonest type of SF3B1 mutation in MDS. Sf3b1K700E/+ animals had impaired erythropoiesis and progressive anemia without ringed sideroblasts, as well as reduced hematopoietic stem cell numbers and host-repopulating fitness. To understand the molecular basis of these observations, we analyzed global RNA splicing in Sf3b1K700E/+ hematopoietic cells. Aberrant splicing was associated with the usage of cryptic 3′ splice and branchpoint sites, as described for human SF3B1 mutants. However, we found a little overlap between aberrantly spliced mRNAs in mouse versus human, suggesting that anemia may be a consequence of globally disrupted splicing. Furthermore, the murine orthologues of genes associated with ring sideroblasts in human MDS, including Abcb7 and Tmem14c, were not aberrantly spliced in Sf3b1K700E/+ mice. Our findings demonstrate that, despite significant differences in affected transcripts, there is overlap in the phenotypes associated with SF3B1-K700E between human and mouse. Future studies should focus on understanding the basis of these similarities and differences as a means of deciphering the consequences of spliceosome gene mutations in MDS.

Short telomere length and its correlation with gene mutations in myelodysplastic syndrome

BackgroundTelomere erosion can lead to genomic instability and cancer progression. It has been suggested that the shortest telomere, not the average telomere length (TL), is critical for cell viability. Some studies have shown shorter TL in myelodysplastic syndrome (MDS) patients but the critically short telomeres, the variability of TL within individual patient has not been evaluated. Thus, we aimed to investigate the TL of MDS patients and assessed the association of TL with recurrent genetic mutations in MDS.MethodsWe measured the TL of bone marrow nucleated cells for diagnostic samples at a single-cell level by quantitative fluorescence in situ hybridization (Q-FISH) for 58 MDS patients and analyzed the minimum, median, average, standard deviation, average of the 0th to 10th percentile TL within a patient, and the proportion of cells with TL that is shorter than the lowest 10th percentile of the normal control (NC). The correlations of TL to clinical parameters, cytogenetic results, and genetic mutations were assessed.ResultsMDS patients showed eroded telomeres and narrow distribution compared to the NC (P < 0.001, P = 0.018, respectively). Patients with mutation showed significantly lesser cells with short TL, below the lowest 10th percentile of the NC (P = 0.017), but no differences in TL were found according to mutations/cytogenetic abnormalities except for CSF3R mutation. However, those patients with a high percentage (≥80 %) of cells with short TL showed poorer overall survival (P = 0.021), and this was an independent prognostic factor, along with TP53, U2AF1 mutation, and high BM blast count (P = 0.044, 0.001, 0.004, 0.012, respectively).ConclusionsThe shortest TL, which determines the fate of the cell, was significantly shorter, and higher burden of cells with short TL were found in MDS, which correlated with poor survival, suggesting the need to measure TL in single cells by Q-FISH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0287-9) contains supplementary material, which is available to authorized users.

Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis.

Genomic analyses of the myeloid malignancies and clonal disorders of hematopoiesis that may give rise to these disorders have identified that mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are among the most common targets of somatic mutations. These spliceosomal mutations often occur in a mutually exclusive manner with one another and, in aggregate, account for the most frequent class of mutations in patients with myelodysplastic syndromes (MDSs) in particular. Although substantial progress has been made in understanding the effects of several of these mutations on splicing and splice site recognition, functional connections linking the mechanistic changes in splicing induced by these mutations to the phenotypic consequences of clonal and aberrant hematopoiesis are not yet well defined. This review describes our current understanding of the mechanistic and biological effects of spliceosomal gene mutations in MDSs as well as the regulation of splicing throughout normal hematopoiesis.

Interpretation of World Health Organization reclassification of myelodysplastic syndromes: reports from the 57th American Society of Hematology annual meeting

Progress of World Health Organization (WHO) reclassification of myelodysplastic syndromes (MDS) in the 57th American Society of Hematology annual meetings were reviewed. A revision to the 4th edition of the WHO classification of MDS will be enacted in mid-2016. Based on recommendations of the Clinical Advisory Committee, proposals for change included abandoning the routine names of 'refractory anemia/cytopenia', expressing the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. Key words: Myelodysplastic syndromes; World Health Organization classification; American Society of Hematology annual meeting

Gene mutations in myelodysplastic syndromes.

Recent progress in next generation sequencing technologies has enabled us to investigate somatic mutations throughout the coding regions of myelodysplastic syndromes (MDS), and have likely provided us with almost the entire spectrum of driver mutations responsible for this disease. As shown by numerous recent studies, such frequent mutations play an important role in the leukemogenesis of MDS. In the first part of this review, we comprehensively describe the characteristics and frequencies of the most prevalent mutations already confirmed as drivers in MDS. Second, we focus on the associations between karyotypic abnormalities and somatic mutations involving chromosomes 5 and 7. In particular, CSNK1A1 mutations are the most recently identified among the 5q- syndromes. Finally, we summarize recently reported findings on the functional effects of frequent splice factor mutations on splicing defects, which have been clarified by multiple institutions.

Reclassifying myelodysplastic syndromes: what's where in the new WHO and why.

A revision to the 4th edition of the WHO Classification of myelodysplastic syndromes (MDSs), originally published in 2008, is expected in mid-2016. Based on recommendations of a Clinical Advisory Committee, the revision will aim to incorporate new discoveries in MDS that impact existing disease categories. Although the basic diagnostic principles of the WHO classification remain unchanged, several changes to the classification are proposed. All revisions are considered preliminary until the actual publication of the monograph and online document. Proposals for change include abandoning the routine use of "refractory anemia/cytopenia" in the various disease names, including the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying most cases of the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. This review will provide details of the major proposed changes as well as rationale for the revisions.