HAEM5:Myelodysplastic/myeloproliferative neoplasm, NOS

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent 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.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). 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); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. 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)*

Ruth MacKinnon PhD

Victorian Cancer Cytogenetics Service

Melbourne, Australia

WHO Classification of Disease

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

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	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). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

editv4:Chromosomal Rearrangements (Gene Fusions)

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• None identified
• BCR-ABL1 fusion should be excluded
• Absence of PDGFRA, PDGFRB and FGFR1 rearrangements, absence of PCM1-JAK2 fusion

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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)

• Prognosis is variable and not well documented
• There are few data regarding an appropriate prognostic scoring system , but IPSS-R or IPSS have been prognostically useful
• Median overall survival (OS) from various reports: 80 months ; 21.8 months ; 12 months
• Leukaemia-free survival: 18.9 months ; 10.8 months
• Leukaemic transformation: 10% ; 16% after a median of 10.8 months ; 
  • ASXL1/SRSF2 co-mutation is a significant risk factor
• Abnormal karyotype associated with inferior OS
• ASXL1, EZH2, STAG2 mutations associated with shorter OS
• Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions .
  • Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo et al. :
    • 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 .

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: 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 references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH

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One study identified very few recurrent gains and losses below the level of cytogenetic detection .

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4: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 ; 48/102 ; 23/65 ; 43/85 )
• Complex karyotype 10% across three studies (12/102 ; 2/65 ; 10/85 )
• 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 . It is the only cytogenetic abnormality mentioned in the MDS/MPN-U section of the 2016 edition of the WHO classification . It is well documented in MDS/MPN with some cases meeting the criteria for atypical CML (aCML), and others justifying an MDS/MPN-U classification . Data on incidence are rare; one case in 65 was reported in one study (1.5%) . Six cases were reported in a series of 551 MDS/MPN which included both aCML and MDS/MPN-U . Meggendorfer et al found a highly significant association between i(17q) and SETBP1 mutations. SETBP1 mutation is strongly correlated with aCML , and was found in about a third of the aCML-like subcategory of MDS/MPN-U .
  • + 8
    • 23% across two studies (26/102 ; 12/65 )
    • isolated +8, 16% across two studies (17/102 ; 13/85 )
  • -7/del(7q)
    • 10% across two studies (12/102 ; 4/65 )
    • isolated -7/del(7q), 5% (5/102 )

• Excludes any case with isolated del(5q) (even if JAK2 is mutated) - these should be classified as MDS with isolated del(5q).

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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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, 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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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 .

No mutations are specific for any MDS/MPN, including MDS/MPN-U .

The WHO in 2017 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%* ; 53%
• TET2: 27% ; 37%
• JAK2: 25% ; 25%
  • V617F ; 18%
• SRSF2: 23% ; 23%
  • P95 residue
• EZH2: 17% ; 25%
• U2AF1: 13% ;19%
  • most mutatons in Q157
• RUNX1: 13% ; 17%
• SF3B1: 12% 11%
• ZRSR2: 11% ; 5%
• SETBP1: 11% ;12%
• NRAS: 10% ; 4%
• DNMT3A: 9% ; 13%
• TP53: 8% ;12%
• STAG2: 5% ; 16%
• CSF3R: 5% ; 5%
• ZBTB33: 5%
  • novel to MDS/MPN-U
• CBL: 4% ; 6%

*Frequencies from Figure 1 in 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 :

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

1. CMML-like (TET2/SRSF2)
2. aCML-like (ASXL1/EZH2)
3. MDS/MPN-RS-T-like (SF3B1 or DNMT3A/SF3B1)
4. TP53 sub-category (mono- or bi-allelic TP53 mutation; more anaemia and higher blast count)
5. 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 .

If a SF3B1 mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts .

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 .

There is a significant likelihood of AML developing if there is ASXL1 and SRSF2 co-mutation .

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Epigenomic Alterations

Not known

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

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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• Major drivers / early mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SRSF2)
• Secondary mutations in signaling pathway genes (JAK2)

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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 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

*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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “Myelodysplastic/myeloproliferative neoplasm, NOS”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Myelodysplastic/myeloproliferative_neoplasm,_NOS.