Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis
Haematolymphoid Tumours (5th ed.)
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editHAEM5 Conversion NotesThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Myelodysplastic/Myeloproliferative Neoplasms with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T).
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
Anamaria Munteanu, MD, Ph.D, Harbor-UCLA Medical Center, Fabiola Quintero-Rivera, University of California Irvine
Cancer Category / Type
Tumors of hematopoietic and lymphoid tissue
Cancer Sub-Classification / Subtype
MDS/MPN overlap syndromes
Definition / Description of Disease
MDS/MPN-RS-T is a MDS/MPN with more than 15% ring sideroblasts and persistent thrombocytosis (more than 450 x 10 9/L platelets). It generally presents with anemia and erythroid dysplasia and SF3B1 mutation is present in 80% of cases. Other diagnosis criteria consider the number of blasts: <1% peripheral blood leukocytes and <5% of nucleated cells in bone marrow. For diagnosis of MDS/MPN-RS-T we must exclude cases with prior diagnosis of MDS, MPN or MDS/MPN, as well as therapy related myeloid neoplasm. Exception are cases of MDS-RS which transform in MDS/MPN RS-T[1][2]
Specific genetic alterations must also be absent: BCR-ABL1 fusion, PDGFRA, PDGFRB, FGFR1, PCM1-JAK2 rearrangements, t(3;3)(q21q26), inv(3)(q21q26) or del(5q).
Synonyms / Terminology
Older terminology includes: Refractory anemia with ring sideroblasts and marked thrombocytosis
Epidemiology / Prevalence
Median patient age is 71-75 years old at diagnosis, with slight female prevalence.
Clinical Features
Put your text here and fill in the table (Instruction: Can include references in the table)
| Signs and Symptoms | EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.Symptoms and clinical features are related to anemia, iron overload and thrombocytosis. Thrombocytemia manifests with thrombosis/hemorrhage. Differential diagnosis for thrombocytosis is Essential Thromocytopenia (ET) or reactive thrombocytosis.
For the presence of ring sideroblasts differential diagnosis includes alcohol, toxins such as lead or zinc, drugs such as isoniazid, chloramphenicol linezolid, penicillamine and other conditions such as pyridoxine deficiency, copper deficiency, or hereditary sideroblastic anemia[3].
Ring sideroblasts are abnormal erythroid lineage precursors with increased mitochondrial iron deposits forming siderotic granules. A minimum of five distinct siderotic granules must be present, involving at least one third of the nuclear circumference.
Sites of Involvement
Peripheral blood and bone marrow involvement are consistently present, splenic and hepatic involvement are less frequent.
Morphologic Features
Normochromic macrocytic anemia,
Thrombocytosis with anisocytosis
Erythroid lineage dysplasia-nuclear segmentation, or megaloblastoid features;
Hemosiderin laden macrophages.
Blast count: Less than 1% peripheral blood leukocytes.
Increased erythroid precursors with ineffective erythropoiesis
Increased number of large mature megakaryocytes with dysplastic features and hyperlobulated nuclei
Bone marrow fibrosis
More than 15% ring sideroblasts
Blast count <5% of nucleated cells in bone marrow
Immunophenotype
| Finding | Marker |
|---|---|
| Positive (universal) | Ring sideroblasts positive with Prussian-blue |
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.No chromosomal rearrangements for MDS/MPN-RS-T
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
The presence of SF3B1 and JAK2 mutations is correlated with better prognosis and longer survival. Mutations in ASXL1, SETBP1 and EZH2 have negative prognostic significance [3][4]. Abnormal karyotypes, although rare, correlate with very poor outcome [4]. Disease outcome: overall survival is better than in patients with MDS-RS-SLD, but worse than in patients with MPN-ET. There is low risk of converging to leukemic forms.[1][3]
Treatment: transfusions, recombinant human erythropoietin for anemia. The use of Lenalidomide is controversial, while, the use of Luspatercept- a novel erythroid maturation agent is not an established treatment option. Aspirin for thrombocytosis. Hydroxyurea is the preferred cytoreductive agent [3]
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.No genomic gain/loss for MDS/MPN-RS-T
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.No recurrent chromosomal aberrations for MDS/MPN-RS-T. However, abnormalities have been reported in 10% of patients. Trisomy 8 and loss of Y are the most common changes.[4]
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.The presence of concomitant mutations in SF3B1 and JAK2 V617F support the diagnosis of MDS/MPN-RS-T; less commonly encountered are SF3B1 and CALR or SF3B1 and MPL [5][4].
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other) SF3B1 RNA splicing 85-97% JAK2 Cell signaling 37-50% TET2 Epigenetic regulator 25% DNMT3A Epigenetic regulator 15% ASXL1 Epigenetic regulator 10-20% IDH2 Epigenetic regulator Other Mutations
In less than 10%, SRSF2, U2AF1, ZRSR2, EZH2, IDH2, ETV6, RUNX1, SETBP1, HEPHL1 and PAFAH2
Type Gene/Region/Other Concomitant Mutations SF3B1 and JAK2 V617F; SF3B1 and CALR; SF3B1 and MPL; SF3B1-DNMT3A Founder mutations SF3B1, DNMT3A Secondary Mutations JAK2, SH2B3, MPL Mutually Exclusive JAK2, CALR, MPL
Epigenomic Alterations
Put your text here
Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.SF3B1 gene mutations are present in over 80% of patients [3]. Somatic mutation in SF3B1 leads to abnormal ABCB7 protein, accumulation of mitochondrial iron and ineffective erythropoiesis, with formation of ring sideroblasts[6]. Mutations in JAK2 correlate with increased platelet count.[4]
Genetic Diagnostic Testing Methods
Gene sequencing.
Flow cytometry to identify abnormal erythroid precursors
Familial Forms
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Additional Information
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Links
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References
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- ↑ 1.0 1.1 1.2 1.3 Arber DA, et al., (2017). MDS/MPN with ring sideroblasts and thrombocytosis, 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, p93-94
- ↑ 2.0 2.1 2.2 Bone Marrow Pathology. Kathryn Foucar, Kaaren Reichard, David Czuchlewski, ASCP Press, 2020, Calssification of MDS/MPN, MDS/MPN with ring sideroblasts and thrombocytosis p383-384.
- ↑ 3.0 3.1 3.2 3.3 3.4 Mm, Patnaik; et al. (2019). "Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management"". doi:10.1002/ajh.25397. PMC 6408294. PMID 30618061.CS1 maint: PMC format (link)
- ↑ 4.0 4.1 4.2 4.3 4.4 L, Palomo; et al. (2020). "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms". PMID 32573691 Check
|pmid=value (help). - ↑ S, Jeromin; et al. (2015). "Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations". doi:10.3324/haematol.2014.119032. PMC 4380732. PMID 25527566.CS1 maint: PMC format (link)
- ↑ M, Cazzola; et al. (2013). "Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms". doi:10.1182/blood-2012-09-399725. PMC 3790951. PMID 23160465.CS1 maint: PMC format (link)
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Myelodysplastic/myeloproliferative_neoplasm_with_SF3B1_mutation_and_thrombocytosis.