HAEM5:Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This 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

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

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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 Features

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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.

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

Peripheral blood:

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.

Bone marrow :

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)

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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)

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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 . Abnormal karyotypes, although rare, correlate with very poor outcome . 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.

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

Individual Region Genomic Gain / Loss / LOH

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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/LOH

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No genomic gain/loss for MDS/MPN-RS-T

Characteristic Chromosomal Patterns

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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 / Patterns

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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.

Gene Mutations (SNV / INDEL)

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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)

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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 .

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

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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 Involved

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SF3B1 gene mutations are present in over 80% of patients . Somatic mutation in SF3B1 leads to abnormal ABCB7 protein, accumulation of mitochondrial iron and ineffective erythropoiesis, with formation of ring sideroblasts. Mutations in JAK2 correlate with increased platelet count.

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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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.