HAEM4:Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Xiaolin Hu, Ph.D., Teresa Smolarek, Ph.D, FACMG

Cancer Category/Type

Myelodysplastic Syndrome (MDS)

Cancer Sub-Classification / Subtype

MDS with Ring Sideroblasts and Multilineage Lineage Dysplasia (MDS-RS-MLD)

Definition / Description of Disease

MDS-RS-MLD is a subtype of MDS-RS which is features with the presence of ≥ 15% ring sideroblasts (RS) in erythroid precursor cells or ≥ 5% RS when SF3B1 mutation is present. In prior version of WHO classification, it set refractory anaemia with ring sideroblasts (RARS) as one group and did not differentiate MDS-RS-SLD with MDS-RS-MLD. In 2016 WHO criteria, MDS-RS-MLD and MDS-RS-SLD were recognized as two separate subtypes of MDS-RS. Compared to MDS-RS-SLD that mainly affects erythroid lineage, MDS-RS-MLD usually has more than one cytopenia and more than two dysplasia in the three myeloid lineages such as erythroid, granulocytic and megakaryocytic lineages. According to 2016 WHO criteria, bone marrow (BM) blasts should be <5% and peripheral blood (PB) blast content should be <1%. In addition, MDS-RS is usually lack of Auer rods, and MDS with isolated del(5q) or RS with secondary causes must be excluded. Ring sideroblasts are erythroid precursor cells in which iron laden mitochondria form a perinuclear ring that can be visualized as blue granules by Prussian blue staining. RS can be found in other clonal neoplasms such as myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Synonyms / Terminology

Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS)

Epidemiology / Prevalence

• MDS-RS mainly affects elderly people with a median age of 60-73 years
• MDS-RS-MLD accounts for approximately 13% of all MDS cases
• No major sex predilection.

Clinical Features

• Usually present with bicytopenia or pancytopenia.
• Frequently has a higher IPSS-R score than MDS-RS-SLD.
• Symptoms with iron overload may be seen.

Sites of Involvement

• Primarily involves peripheral blood and bone marrow
• Liver and spleen may be affected by iron overload

Morphologic Features

Dyserythropoiesis is the most common dysplasia. In addition, significant dysplasia usually ≥ 10% can be seen in more than one non-erythroid lineages. Morphology of MDS-RS-MLD will be similar to those of MDS with multiple lineage dysplasia (MDS-MLD) except for the presence of ≥ 15% ring sideroblasts.

Immunophenotype

Currently, morphologic evaluation remains the gold standard in diagnosis of MDS. Immunophenotyping provides supportive evidence to clarify the blasts nature and percentage . Flow cytometry may be used to characterize erythroid precursor cells. Della Porta M.G. et al proposed a set of immunophenotypic variables such as cytosolic H-ferritin, CD71 and CD105 to predict functionally aberrant erythropoietic precursors. They also reported mitochondrial ferritin (MtF) correlates well with the presence of ring sideroblasts and suggested MtF can be used in diagnosis of sideroblastic anemia .

Finding	Marker
Positive (universal)	EXAMPLE CD1=
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Put your text here and/or fill in the table

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 5%
EXAMPLE t(8;21)(q22;q22)	EXAMPLE 5'RUNX1 / 3'RUNXT1	EXAMPLE der(8)	EXAMPLE 5%

Characteristic Chromosomal Aberrations / Patterns

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Genomic Gain/Loss/LOH

About 50% of MDS-RS-MLD have cytogenetic abnormalities. High-risk abnormalities such as loss of chromosome 7 can be seen in this category.

Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:0-1000000
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

Somatic mutations in SF3B1 have been reported in several myeloid malignancies, especially MDS-RS. High occurrence rate of SF3B1 mutations has been observed in about 80% of patients with MDS-RS-SLD and 40% of patients with MDS-RS-MLD . Most genetic alterations in SF3B1 are heterozygous missense variants that tend to cluster in C-terminal HEAT domains (residues 622–781). K700E accounts for 50% of these variants. Additional hotspots residues include 622, 625, 662 and 666. SF3B1 mutation is highly correlate with the presence of BM RS, and therefore was incorporated into 2018 WHO classification of MDS as a diagnostic criteria for MDS-RS when BM RS is over 5% or more. However, SF3B1 mutation alone does not confer diagnosis of MDS-RS. Several studies have demonstrated SF3B1 has a favorable prognostic impact .

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Epigenomics (Methylation)

Genes involved in epigenetic regulation are frequently mutated in MDS such as TET2, DNMT3A, IDH1, IDH2, AXSL1, and EZH2 . These genes play a role in DNA methylation and chromatin modification as well as regulating gene expression. In low risk MDS such as MDS-RS, mutations in these genes can coexist with SF3B1 mutation and seem to be associated with MDS-RS-MLD .

Genes and Main Pathways Involved

SF3B1 gene encodes a protein that is part of the U2 snRNP protein complex which functions as splicing machinery to regulate pre-mRNA maturation. Studies have shown that mutated SF3B1 tends to utilize alternative branch point sequence to direct the U2 snRNP to an altered 3' splice site and therefore produces aberrantly spliced mRNAs which are frequently subjected to nonsense-mediated decay . The mechanisms of how spliceosome defect leads to accumulation of BM RS are still unclear. In patients with SF3B1 mutations, the transcriptome profile shows that genes involved in mitochondrial ribosome and electron transport chain were significantly down-regulated . ABCB7, a transporter gene that mediate heme homeostasis, previously known to cause congenital sideroblastic anemia, was found to be down-regulated by aberrant splicing in SF3B1 mutated erythroid blasts . A recent study showed a variant transcript of erythroferrone was elevated in MDS patients with an SF3B1 mutations and is responsible for hepcidin suppression and iron overload .

In addition to spliceosome pathway, DNA methylators, chromatin modifiers and transcription factors are among the most frequently mutated categories in MDS-RS. The prognostic and therapeutic values remain to be elucidated.

Diagnostic Testing Methods

• Morphology

• Blood test
• BM aspirate
• Iron staining: Prussian blue (Peals reaction)
• Histomorphology
• Cytogenetics/FISH studies
• Molecular analysis: Sanger sequencing, Next Generation Sequencing

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

The diagnosis of MDS-RS-MLD needs to meet MDS-RS diagnosis criteria and in addition include:

• ≥ 10% dysplasisa in two or more myeloid lineages (MDS-RS-MLD)

• Exclusions include: non-clonal dysplasia, therapy-related myeloid neoplasm, isolated del(5q), and secondary causes of RS

Prognosis:

• IPSS (international prognostic scoring system) , R-IPSS (revised IPSS) and WPSS (WHO classification based prognostic scoring system) are widely used scoring systems to evaluate MDS prognosis.

• The median survival of MDS-RS-MLD is 28 months [WHO].

• 8% in MDS-RS-MLD[WHO] cases progress to acute myeloid leukemia.

• SF3B1 mutation is thought to have favorable prognosis when no other adverse factors in present.

• Mutations in the TP53, EZH2, ETV6, RUNX1, and ASXL1 are reported to be associated with shorter survival . SF3B1^mutant/ASXL1^wildtype genotype is of the most favorable prognosis whereas ASXL1 independently confers adverse prognosis .

Therapeutic Implications:

• Allogeeic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with MDS.

• Treatment of anemia: recombinant human erythropoietin, darbepoetin

• Immunomodulatory agents: Lenalidomide, TGF-β inhibitors such as Sotatercept and Luspatercept.

• Iron chelation therapy if iron overload.Hypomethylating agents are under investigation.

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Familial Forms

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Other Information

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Links

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References

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EXAMPLE Book

1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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