View source for HAEM5:Myelodysplastic/myeloproliferative neoplasm, NOS

{{DISPLAYTITLE:Myelodysplastic/myeloproliferative neoplasm, NOS}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable]].
}}</blockquote>

<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); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. 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)*==
Ruth MacKinnon PhD

Victorian Cancer Cytogenetics Service

Melbourne, Australia

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!Structure
!Disease
|-
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|Myeloid proliferations and neoplasms
|-
|Family
|Myelodysplastic/myeloproliferative neoplasms
|-
|Type
|N/A
|-
|Subtype(s)
|Myelodysplastic/myeloproliferative neoplasm, NOS
|}

==Definition / Description of Disease==

MDS/MPN-U are a heterogeneous group of myeloid neoplasms meeting the criteria for MDS/MPN at onset, without the defining features of one of the other categories of MDS/MPN, i.e. chronic myelomonocytic leukaemia (CMML) juvenile myelomonocytic leukaemia (JMML), atypical chronic myeloid leukaemia, ''BCR-ABL1''-negative (aCML) or myelodysplastic / myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). <ref name=":0">Orazi A, et al., (2017). Myelodysplastic / myeloproliferative neoplasm, unclassifiable, 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, p95-96.</ref><ref name=":1">{{Cite journal|last=Ti|first=Mughal|last2=Nc|first2=Cross|last3=E|first3=Padron|last4=Rv|first4=Tiu|last5=M|first5=Savona|last6=L|first6=Malcovati|last7=R|first7=Tibes|last8=Rs|first8=Komrokji|last9=Jj|first9=Kiladjian|date=2015|title=An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/26341525/|language=en|doi=10.3324/haematol.2014.114660|pmc=PMC4800699|pmid=26341525}}</ref> 

MDS/MPN-U is the most poorly characterised of the MDS/MPN subgroups <ref name=":2">{{Cite journal|last=P|first=Bose|last2=A|first2=Nazha|last3=Rs|first3=Komrokji|last4=Kp|first4=Patel|last5=Sa|first5=Pierce|last6=N|first6=Al-Ali|last7=A|first7=Sochacki|last8=A|first8=Shaver|last9=W|first9=Ma|date=2018|title=Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable|url=https://pubmed.ncbi.nlm.nih.gov/30242087/|language=en|doi=10.1182/blood-2018-05-848473|pmc=PMC6236463|pmid=30242087}}</ref>.

*< 20% blasts in the peripheral blood and bone marrow
*Clinical and morphological features of a category of MDS 
**'''excluding''' any case meeting the criteria for MDS with isolated del(5q)
*Platelet count of ≥ 450 ×10/L with bone marrow megakaryocytic proliferation and/or a white bood cell count of ≥ 13 × 10<sup>9</sup>/L
*Myelodysplastic / myeloproliferative features not explained by recent cytotoxic or growth factor therapy
*Excludes cases with ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangement and ''PCM1-JAK2'' <ref name=":0" />

When an underlying MPN has not been identified, the category of MDS/MPN-U is appropriate. <ref name=":0" />

Cases with features of MDS/MPN-U may arise due to prior exposure to treatment and are included in the [[HAEM5:Myeloid neoplasm post cytotoxic therapy|Therapy-related myeloid neoplasms]] (t-MN).

Well-defined MPN which subsequently develop dysplastic features and progress to a more aggressive phase are excluded from this category.

Palomo ''et al.'' <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> proposed sub-categories of MDS/MPN-U based on the molecular signature. See [[Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable#Gene Mutations .28SNV.2FINDEL.29|Gene Mutations]] below. 

==Synonyms / Terminology==

*Chronic myelodysplastic / myeloproliferative disease (no longer used)
*Mixed myeloproliferative / myelodysplastic syndrome, unclassifiable
*Overlap syndrome, unclassifiable <ref name=":0" /><ref name=":1" />

==Epidemiology / Prevalence==

*Less than 5% of myeloid malignancies<ref>{{Cite journal|last=L|first=Cannella|last2=M|first2=Breccia|last3=R|first3=Latagliata|last4=A|first4=Frustaci|last5=G|first5=Alimena|date=2008|title=Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification|url=https://pubmed.ncbi.nlm.nih.gov/17709138/|language=en|pmid=17709138}}</ref>
*Median age: reports vary from 70 <ref name=":1" /> to 75 <ref name=":2" />
*Male:female ratio 2:1 <ref name=":1" /><ref name=":3" />

==Clinical Features==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)

<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)

<span class="blue-text">EXAMPLE:</span> Fatigue

<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}


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

*Overlap with [[HAEM4:Myelodysplastic Syndromes (MDS)|MDS]] and [[HAEM4:Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />
*Clinically the most heterogeneous of the MDS/MPN <ref name=":3" />
*Does not have features that define it as belonging to any of the other categories of MDS/MPN <ref name=":0" /><ref name=":1" />

</blockquote>
==Sites of Involvement==

*Peripheral blood and bone marrow always involved
*Extramedullary tissues may be involved <ref name=":0" />

==Morphologic Features==

Co-occurrence of myeloid lineages with (i) ineffective and/or dysplastic proliferation and (ii) effective proliferation with or without dysplasia

*Usually with anaemia, with or without macrocytosis
*Thrombocytosis (platelets ≥ 450 x 10<sup>9</sup>/L) or leucocytosis (white blood cells ≥ 13 x 10<sup>9</sup>/L)
*Dysgranulopoiesis in about 50% of cases
*Giant or hypogranular platelets in some
*Dysmegakaryopoiesis with megakaryocytes resembling those in MDS in >50% of cases, otherwise varying proportions of MDS-like and MPN-like megakaryocytes
*No dysmegakaryopoiesis in <10% of cases
*Blasts < 20% in bone marrow and peripheral blood
*Proliferation in any or all of myeloid lineages in bone marrow biopsy
*≥ 10% of at least one cell line <ref name=":0" />

Palomo ''et al.''<nowiki/>'s MDS/MPN-U sub-categories  defined by molecular profile <ref name=":3" /> (see Gene Mutations below) tend to have:

*CMML-like: higher monocyte count
*aCML-like: higher white blood cell count
*MDS/MPN-RS-T-like: higher ring sideroblast percentage
*''TP53'': more anaemia and higher blast percentage
*other: ''JAK2'' mutations correlated with thrombocytosis

==Immunophenotype==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|-
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
|}


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

May be similar to that of [[HAEM4:Myelodysplastic Syndromes (MDS)|MDS]] or [[HAEM4:Myeloproliferative Neoplasms (MPN)|MPN]] <ref name=":0" />

</blockquote>
==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
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<span class="blue-text">EXAMPLE:</span>

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.}}

*None identified
*''BCR-ABL1'' fusion should be excluded
*Absence of ''PDGFRA'', ''PDGFRB'' and ''FGFR1'' rearrangements, absence of ''PCM1-JAK2'' fusion <ref name=":0" />

</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)}}

*Prognosis is variable and not well documented <ref name=":0" />
*There are few data regarding an appropriate prognostic scoring system <ref name=":0" />, but IPSS-R <ref name=":2" />or IPSS <ref name=":5" /> have been prognostically useful
*Median overall survival (OS) from various reports: 80 months <ref name=":3" />; 21.8 months <ref name=":4" />; 12 months <ref name=":2" />
*Leukaemia-free survival: 18.9 months <ref name=":4" />; 10.8 months <ref name=":2" />
*Leukaemic transformation: 10% <ref name=":3" />; 16% after a median of 10.8 months <ref name=":2" />;  
**ASXL1/SRSF2 co-mutation is a significant risk factor <ref name=":2" />
*Abnormal karyotype associated with inferior OS <ref name=":3" />
*''ASXL1, EZH2, STAG2'' mutations associated with shorter OS <ref name=":2" /><ref name=":3" />
*Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions <ref name=":3" />.
**Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo ''et al.'' <ref name=":3" />: 
***MDS/MPN-RS-T-like: most favourable prognosis
***aCML-like: high risk
***"TP53": least favourable prognosis
*“Treatment is based on therapies used for MDS or MPN and is guided by symptoms and/or cytopenias” and can include growth factors for leukocytosis or cytoreductive therapies for cytopenias <ref name=":0" />.

</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. Do not delete table.'') </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
|-
|<span class="blue-text">EXAMPLE:</span>

7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>

chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>

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).
|-
|<span class="blue-text">EXAMPLE:</span>

8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>

chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>

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.}}

One study identified very few recurrent gains and losses below the level of cytogenetic detection <ref name=":3" />. 

</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. Do not delete table.'')</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
|-
|<span class="blue-text">EXAMPLE:</span>

Co-deletion of 1p and 18q
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>

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.}}

*None specific to MDS/MPN-U
*Abnormal karyotype 43% across four studies (11/38 <ref>{{Cite journal|last=M|first=Meggendorfer|last2=S|first2=Jeromin|last3=C|first3=Haferlach|last4=W|first4=Kern|last5=T|first5=Haferlach|date=2018|title=The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/29700173/|language=en|doi=10.3324/haematol.2017.183160|pmc=PMC5927999|pmid=29700173}}</ref>; 48/102 <ref name=":3" />; 23/65 <ref name=":4">{{Cite journal|last=Sa|first=Wang|last2=Rp|first2=Hasserjian|last3=Ps|first3=Fox|last4=Hj|first4=Rogers|last5=Jt|first5=Geyer|last6=D|first6=Chabot-Richards|last7=E|first7=Weinzierl|last8=J|first8=Hatem|last9=J|first9=Jaso|date=2014|title=Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/24627528/|language=en|doi=10.1182/blood-2014-02-553800|pmc=PMC4067498|pmid=24627528}}</ref>; 43/85 <ref name=":5">{{Cite journal|last=Cd|first=DiNardo|last2=N|first2=Daver|last3=N|first3=Jain|last4=N|first4=Pemmaraju|last5=C|first5=Bueso-Ramos|last6=Cc|first6=Yin|last7=S|first7=Pierce|last8=E|first8=Jabbour|last9=Je|first9=Cortes|date=2014|title=Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy|url=https://pubmed.ncbi.nlm.nih.gov/24492324/|language=en|doi=10.1038/leu.2014.8|pmc=PMC3981947|pmid=24492324}}</ref>)
*Complex karyotype 10% across three studies (12/102 <ref name=":3" />; 2/65 <ref name=":4" />; 10/85 <ref name=":5" />)
*Specific abnormalities:
**Isochromosome of 17q (commonly referred to as i(17q) but correctly written as i(17)(p11.2)) has gain of 17q, gain of 17p from the 17p11.2 breakpoint to the centromere; and loss of 17p from the telomere to the 17p11.2 breakpoint, including ''TP53'' <ref>{{Cite journal|last=Barbouti|first=Aikaterini|last2=Stankiewicz|first2=Pawel|last3=Nusbaum|first3=Chad|last4=Cuomo|first4=Christina|last5=Cook|first5=April|last6=Höglund|first6=Mattias|last7=Johansson|first7=Bertil|last8=Hagemeijer|first8=Anne|last9=Park|first9=Sung-Sup|date=2004|title=The Breakpoint Region of the Most Common Isochromosome, i(17q), in Human Neoplasia Is Characterized by a Complex Genomic Architecture with Large, Palindromic, Low-Copy Repeats|url=https://linkinghub.elsevier.com/retrieve/pii/S0002929707619399|journal=The American Journal of Human Genetics|language=en|volume=74|issue=1|pages=1–10|doi=10.1086/380648|pmc=PMC1181896|pmid=14666446}}</ref> <ref>{{Cite journal|last=T|first=Fioretos|last2=B|first2=Strömbeck|last3=T|first3=Sandberg|last4=B|first4=Johansson|last5=R|first5=Billström|last6=A|first6=Borg|last7=Pg|first7=Nilsson|last8=H|first8=Van Den Berghe|last9=A|first9=Hagemeijer|date=1999|title=Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations|url=https://pubmed.ncbi.nlm.nih.gov/10381517/|language=en|pmid=10381517}}</ref>. It is the only cytogenetic abnormality mentioned in the MDS/MPN-U section of the 2016 edition of the WHO classification <ref name=":0" />. It is well documented in MDS/MPN <ref>{{Cite journal|last=R|first=Kanagal-Shamanna|last2=Ce|first2=Bueso-Ramos|last3=B|first3=Barkoh|last4=G|first4=Lu|last5=S|first5=Wang|last6=G|first6=Garcia-Manero|last7=S|first7=Vadhan-Raj|last8=D|first8=Hoehn|last9=Lj|first9=Medeiros|date=2012|title=Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53|url=https://pubmed.ncbi.nlm.nih.gov/22038701/|language=en|pmid=22038701}}</ref><ref>{{Cite journal|last=McClure|first=R. F.|last2=Dewald|first2=G. W.|last3=Hoyer|first3=J. D.|last4=Hanson|first4=C. A.|date=1999|title=Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course|url=http://doi.wiley.com/10.1046/j.1365-2141.1999.01537.x|journal=British Journal of Haematology|language=en|volume=106|issue=2|pages=445–454|doi=10.1046/j.1365-2141.1999.01537.x|issn=0007-1048}}</ref> with some cases meeting the criteria for atypical CML (aCML), and others justifying an MDS/MPN-U classification <ref name=":0" />. Data on incidence are rare; one case in 65 was reported in one study (1.5%) <ref name=":4" />. Six  cases were reported in a series of 551 MDS/MPN which included both aCML and MDS/MPN-U . Meggendorfer et al <ref name=":7">{{Cite journal|last=M|first=Meggendorfer|last2=U|first2=Bacher|last3=T|first3=Alpermann|last4=C|first4=Haferlach|last5=W|first5=Kern|last6=C|first6=Gambacorti-Passerini|last7=T|first7=Haferlach|last8=S|first8=Schnittger|date=2013|title=SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations|url=https://pubmed.ncbi.nlm.nih.gov/23628959/|language=en|pmid=23628959}}</ref> found a highly significant association between i(17q) and ''SETBP1'' mutations. ''SETBP1'' mutation is strongly correlated with aCML <ref name=":3" /> <ref name=":7" />, and was found in about a third of the aCML-like subcategory of MDS/MPN-U <ref name=":3" />.
**+ 8
***23% across two studies (26/102 <ref name=":3" />; 12/65 <ref name=":4" />)
***isolated +8, 16% across two studies (17/102 <ref name=":3" />; 13/85 <ref name=":5" />)
**-7/del(7q)
***10% across two studies (12/102 <ref name=":3" />; 4/65 <ref name=":4" />)
***isolated -7/del(7q), 5% (5/102 <ref name=":3" />)

*Excludes any case with isolated del(5q) (even if ''JAK2'' is mutated) <ref name=":0" /> - these should be classified as MDS with isolated del(5q).

</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 as 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. Do not delete table.'') </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
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

<span class="blue-text">EXAMPLE:</span>

EGFR; Exon 20 mutations

<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)

<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|<span class="blue-text">EXAMPLE:</span>  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.}}

Amongst the MDS/MPN subtypes, MDS/MPN-U has the most heterogeneous mutation profile. In one study it was most strongly correlated with ''U2AF1'' and ''TP53'' mutations <ref name=":3" />.

No mutations are specific for any MDS/MPN, including MDS/MPN-U <ref name=":3" />.

The WHO in 2017 <ref name=":0" /> listed ''TET2'', ''NRAS'', ''RUNX1'', ''CBL'', ''SETBP1'' and ''ASXL1'' as having relatively high mutation frequencies. Frequencies* of these and the other most common mutations given in recent publications are:

*''ASXL1:'' 29%* <ref name=":2" />; 53% <ref name=":3" />
*''TET2:'' 27% <ref name=":2" />; 37% <ref name=":3" />
*''JAK2:'' 25% <ref name=":2" />; 25% <ref name=":3" />
**V617F <ref name=":2" />; 18% <ref name=":4" />
*''SRSF2:'' 23% <ref name=":2" />; 23% <ref name=":3" />
**P95 residue <ref name=":2" />
*''EZH2:'' 17% <ref name=":2" />; 25% <ref name=":3" />
*''U2AF1:'' 13% <ref name=":2" />;19% <ref name=":3" />
**most mutatons in Q157 <ref name=":2" />
*''RUNX1:'' 13% <ref name=":2" />; 17% <ref name=":3" />
*''SF3B1:'' 12% <ref name=":2" />11% <ref name=":3" />
*''ZRSR2:'' 11% <ref name=":2" />'';'' 5% <ref name=":3" />
*''SETBP1:'' 11% <ref name=":2" />;12% <ref name=":3" />
*''NRAS:'' 10% <ref name=":2" />; 4% <ref name=":3" />
*''DNMT3A:'' 9% <ref name=":2" />'';'' 13% <ref name=":3" />
*''TP53:'' 8% <ref name=":2" />;12% <ref name=":3" />
*''STAG2:'' 5% <ref name=":2" />; 16% <ref name=":3" />
*''CSF3R:'' 5% <ref name=":2" />'';'' 5% <ref name=":3" />
*''ZBTB33:'' 5% <ref name=":3" /> 
**novel to MDS/MPN-U
*''CBL:'' 4% <ref name=":2" />; 6% <ref name=":3" />

<nowiki>*</nowiki>Frequencies from Figure 1 in <ref name=":2" /> are given, since the list in the text does not include all of these genes (the values in the text do not match the values in Figure 1).

Palomo ''et al'' identified specific mutation combinations that mimicked the other MDS/MPN subtypes and allowed MDS/MPN-U to be assigned to one of five MDS/MPN-U sub-categories <ref name=":3" />:  

(The first three are most similar to one of the three other adult subgroups of MDS/MPN) 

#CMML-like (''TET2/SRSF2'')
#aCML-like (''ASXL1/EZH2'')
#MDS/MPN-RS-T-like (''SF3B1'' or ''DNMT3A/SF3B1'')
#TP53 sub-category (mono- or bi-allelic ''TP53'' mutation; more anaemia and higher blast count)
#other (no distinctive signature but enriched for ''U2AF1, JAK2, ASXL1'' mutations; ''JAK2'' mutations correlated with thrombocytosis)

===Other Mutations===
The presence of ''TET2'', ''NRAS'', ''RUNX1'', ''CBL'', ''SETBP1'' or ''ASXL1'' mutation may help confirm a suspected diagnosis <ref name=":0" />.

If a ''SF3B1'' mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts <ref name=":0" />. 

MPN driver mutations (e.g. ''JAK2'', ''MPL'' or ''CALR'' mutation'')'' may be present, but if pre-existing MPN is not documented, an MDS/MPN-U designation is justified <ref name=":0" />.

There is a significant likelihood of AML developing if there is ''ASXL1'' and ''SRSF2'' co-mutation <ref name=":2" />.

</blockquote>
==Epigenomic Alterations==

Not known

==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. Do not delete table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  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.}}

*Major drivers / early mutations in epigenetic regulators (''ASXL1, TET2)'' and splicing factors (''SRSF2'') <ref name=":2" /> <ref name=":3" />
*Secondary mutations in signaling pathway genes (''JAK2'') <ref name=":3" />

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

*Bone marrow aspirate
*Full blood count
*Cytogenetics

==Familial Forms==

Not known

==Additional Information==

Refractory anemia with ring sideroblasts and thrombosis (RARS-T) fell within this category prior to the 2016 WHO edition <ref name=":0" /><ref name=":6">{{Cite journal|last=A|first=Orazi|last2=U|first2=Germing|date=2008|title=The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features|url=https://pubmed.ncbi.nlm.nih.gov/18480833/|language=en|pmid=18480833}}</ref> but now forms a distinct category, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). 

==Links==

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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, NOS”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myelodysplastic/myeloproliferative_neoplasm,_NOS</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases M]]