View source for HAEM5:Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis

{{DISPLAYTITLE:Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 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)]].
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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

Anamaria Munteanu, MD, Ph.D, Harbor-UCLA Medical Center, Fabiola Quintero-Rivera, University of California Irvine

__TOC__

==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 <sup>9</sup>/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<ref name=":0">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</ref><ref name=":1">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.</ref>

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 <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
|'''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)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The 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<ref name=":2">{{Cite journal|last=Mm|first=Patnaik|last2=A|first2=Tefferi|date=2019|title=Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management"|url=https://pubmed.ncbi.nlm.nih.gov/30618061/|language=en|doi=10.1002/ajh.25397|pmc=PMC6408294|pmid=30618061}}</ref>.

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.

</blockquote>
==Sites of Involvement==

Peripheral blood and bone marrow involvement are consistently present, splenic and hepatic involvement are less frequent.

==Morphologic Features==

Peripheral blood<ref name=":0" /><ref name=":1" />: 

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 <ref name=":0" /><ref name=":1" />:

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==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Ring sideroblasts positive with Prussian-blue
|}

==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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).
|}		
			

<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

No chromosomal rearrangements for MDS/MPN-RS-T
</blockquote>


<blockquote class='blockedit'>{{Box-round|title=v4: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 <ref name=":2" /><ref name=":3" />. Abnormal karyotypes, although rare, correlate with very poor outcome <ref name=":3" />. 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.<ref name=":0" /><ref name=":2" />

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 <ref name=":2" />

</blockquote>
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>

{| class="wikitable sortable"
|-
!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).
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}

No genomic gain/loss for MDS/MPN-RS-T
</blockquote>
==Characteristic Chromosomal Patterns==

Put your text here <span style="color:#0070C0">(''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'')</span>

{| class="wikitable sortable"
|-
!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).
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The 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.<ref name=":3" /> 

</blockquote>
==Gene Mutations (SNV / INDEL)==

Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>

{| class="wikitable sortable"
|-
!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).
<br />
|}
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.


<blockquote class='blockedit'>{{Box-round|title=v4: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 <ref>{{Cite journal|last=S|first=Jeromin|last2=T|first2=Haferlach|last3=S|first3=Weissmann|last4=M|first4=Meggendorfer|last5=C|first5=Eder|last6=N|first6=Nadarajah|last7=T|first7=Alpermann|last8=A|first8=Kohlmann|last9=W|first9=Kern|date=2015|title=Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations|url=https://pubmed.ncbi.nlm.nih.gov/25527566/|language=en|doi=10.3324/haematol.2014.119032|pmc=PMC4380732|pmid=25527566}}</ref><ref name=":3">{{Cite journal|last=L|first=Palomo|last2=M|first2=Meggendorfer|last3=S|first3=Hutter|last4=S|first4=Twardziok|last5=V|first5=Adema|last6=I|first6=Fuhrmann|last7=F|first7=Fuster-Tormo|last8=B|first8=Xicoy|last9=L|first9=Zamora|date=2020|title=Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/32573691/|language=en|pmid=32573691}}</ref>.

{| class="wikitable sortable"
|-
!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
{| class="wikitable sortable"
|-
!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
|}

</blockquote>
==Epigenomic Alterations==

Put your text here

==Genes and Main Pathways Involved==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
|-
!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
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}

SF3B1 gene mutations are present in over 80% of patients <ref name=":2" />. Somatic mutation in SF3B1 leads to abnormal ABCB7 protein, accumulation of mitochondrial iron and ineffective erythropoiesis, with formation of ring sideroblasts<ref>{{Cite journal|last=M|first=Cazzola|last2=M|first2=Rossi|last3=L|first3=Malcovati|date=2013|title=Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/23160465/|language=en|doi=10.1182/blood-2012-09-399725|pmc=PMC3790951|pmid=23160465}}</ref>. Mutations in JAK2 correlate with increased platelet count.<ref name=":3" /> 

</blockquote>
==Genetic Diagnostic Testing Methods==

Gene sequencing. 

Flow cytometry to identify abnormal erythroid precursors

==Familial Forms==

Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>

==Additional Information==

Put your text here

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==References==
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==Notes==
<nowiki>*</nowiki>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.
<nowiki>*</nowiki>''Citation of this Page'': “Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myelodysplastic/myeloproliferative_neoplasm_with_SF3B1_mutation_and_thrombocytosis</nowiki>.
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