Anemia as the Main Manifestation of Myelodysplastic Syndromes

Santini, Valeria

doi:10.1053/j.seminhematol.2015.06.002

Cited by 42 publications

(38 citation statements)

References 89 publications

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“…Patients with MDS suffer from refractory anemia, which is a defining feature of this disorder (1, 33). In our study, we demonstrated that expression of U2AF1 S34F in human hematopoietic progenitors results in impaired erythroid differentiation as a result of poor hemoglobinization and reduced growth of erythroid progenitors.…”

Section: Discussionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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Mutations of the splicing factor–encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1S34F expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1S34F induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1S34F altered mRNA splicing of many transcripts that were expressed in both cell types in a lineage-specific manner. In hematopoietic progenitors, the introduction of isoform changes identified in the U2AF1S34F target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor–associated protein, recapitulated phenotypes associated with U2AF1S34F expression in erythroid and granulomonocytic cells, suggesting a causal link. Furthermore, we showed that isoform modulation of H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1S34F MDS cells, suggesting that splicing modulators could be used therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.

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Section: Discussionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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“…When symptomatic, anemia should be promptly treated, avoiding transfusions and improving quality of life (QoL). [17][18][19] With a median age of 71 to 74 years for MDS patients in Western countries, 15 it is evident that chronically low levels of hemoglobin (Hb) can severely impact already frail subjects, causing not only the worsening of cardiac function but also increasing falls and inducing cognitive impairment. Therefore, anemia of MDS constitutes an important social and economic burden.…”

Section: Treatment Of Anemiamentioning

confidence: 99%

“…24 Provided endogenous EPO is measured and is below 500 U/L (see section to follow), treatment with ESAs should start in a timely manner, before transfusion-dependence is established, because the probability to respond is higher for early treated, transfusionindependent patients. 25 Response to ESAs is generally observed within 12 weeks 17 and should not be evaluated before then to avoid missing some cases that show later increases of Hb. Together with optimal doses and periods of treatment, it is important to administer ESAs regularly and without interruptions in order to maintain stable levels of Hb, whose target values are 12 g/dL, traditionally derived from recommendations regarding renal-insufficient and solid tumor patients.…”

Section: Treatment Of Anemiamentioning

confidence: 99%

“…As such, a high percentage of lower-risk MDS patients will respond to ESA treatment, with the highest rates of response (as much as 70%) being obtained, provided selection criteria are followed. 17 Endogenous EPO levels should be ,500 U/L as per the Nordic score 26 (better if ,200 U/L), transfusion requirement should be absent or limited (,2 U/month), cytogenetics normal, marrow blasts absent, and of course IPSS should be low or INT-1. 17,20 Recent evidence indicated that in IPSS lower-risk MDS patients selected with the above-mentioned criteria, application of IPSS-R risk score can refine prediction of response: very low-risk patients responded to ESA therapy in 85% of the cases, compared with 68%, 48%, and 31% of low-, intermediate-, and high-risk scores, respectively.…”

Section: Treatment Of Anemiamentioning

confidence: 99%

“…[48][49][50][51][52] In the end, the majority of patients with lower-risk MDS would require RBC transfusions. 17 Given their relatively long survival, this support therapy is chronic and as such may create long-term side effects, as well as a social and economic burden. 53 Firstly, there are differences in the approach to transfusion therapy.…”

Section: Mds Lower Risk Without Del5qmentioning

confidence: 99%

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Treatment of low-risk myelodysplastic syndromes

Santini

2016

Hematology

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The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

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Targeting ineffective hematopoiesis in myelodysplastic syndromes

Patnaik

2021

American J Hematol

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Anemia as the Main Manifestation of Myelodysplastic Syndromes

Cited by 42 publications

References 89 publications

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Treatment of low-risk myelodysplastic syndromes

Targeting ineffective hematopoiesis in myelodysplastic syndromes

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