Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), Unclassifiable

From Compendium of Cancer Genome Aberrations
Jump to navigation Jump to search

Primary Author(s)*

Ruth MacKinnon PhD

Victorian Cancer Cytogenetics Service

Melbourne, Australia

Cancer Category/Type

Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN)

Cancer Sub-Classification / Subtype

Myelodysplastic / myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)

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). [1][2]

MDS/MPN-U is the most poorly characterised of the MDS/MPN subgroups [3].

  • < 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 × 109/L
  • Myelodysplastic / myeloproliferative features not explained by recent cytotoxic or growth factor therapy
  • Excludes cases with PDGFRA, PDGFRB and FGFR1 rearrangement and PCM1-JAK2 [1]

When an underlying MPN has not been identified, the category of MDS/MPN-U is appropriate. [1]

Cases with features of MDS/MPN-U may arise due to prior exposure to treatment and are included in the 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. [4] proposed sub-categories of MDS/MPN-U based on the molecular signature. See Gene Mutations below.

Synonyms / Terminology

  • Chronic myelodysplastic / myeloproliferative disease (no longer used)
  • Mixed myeloproliferative / myelodysplastic syndrome, unclassifiable
  • Overlap syndrome, unclassifiable [1][2]

Epidemiology / Prevalence

  • Less than 5% of myeloid malignancies[5]
  • Median age: reports vary from 70 [2] to 75 [3]
  • Male:female ratio 2:1 [2][4]

Clinical Features

  • Overlap with MDS and MPN [1]
  • Clinically the most heterogeneous of the MDS/MPN [4]
  • Does not have features that define it as belonging to any of the other categories of MDS/MPN [1][2]

Sites of Involvement

  • Peripheral blood and bone marrow always involved
  • Extramedullary tissues may be involved [1]

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 109/L) or leucocytosis (white blood cells ≥ 13 x 109/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 [1]

Palomo et al.'s MDS/MPN-U sub-categories defined by molecular profile [4] (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


May be similar to that of MDS or MPN [1]

Chromosomal Rearrangements (Gene Fusions)

  • None identified
  • BCR-ABL1 fusion should be excluded
  • Absence of PDGFRA, PDGFRB and FGFR1 rearrangements, absence of PCM1-JAK2 fusion [1]

Characteristic Chromosomal Aberrations / Patterns

  • None specific to MDS/MPN-U
  • Abnormal karyotype 43% across four studies (11/38 [6]; 48/102 [4]; 23/65 [7]; 43/85 [8])
  • Complex karyotype 10% across three studies (12/102 [4]; 2/65 [7]; 10/85 [8])
  • 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 [9] [10]. It is the only cytogenetic abnormality mentioned in the MDS/MPN-U section of the 2016 edition of the WHO classification [1]. It is well documented in MDS/MPN [11][12] with some cases meeting the criteria for atypical CML (aCML), and others justifying an MDS/MPN-U classification [1]. Data on incidence are rare; one case in 65 was reported in one study (1.5%) [7]. Six cases were reported in a series of 551 MDS/MPN which included both aCML and MDS/MPN-U . Meggendorfer et al [13] found a highly significant association between i(17q) and SETBP1 mutations. SETBP1 mutation is strongly correlated with aCML [4] [13], and was found in about a third of the aCML-like subcategory of MDS/MPN-U [4].
    • + 8
      • 23% across two studies (26/102 [4]; 12/65 [7])
      • isolated +8, 16% across two studies (17/102 [4]; 13/85 [8])
    • -7/del(7q)
      • 10% across two studies (12/102 [4]; 4/65 [7])
      • isolated -7/del(7q), 5% (5/102 [4])
  • Excludes any case with isolated del(5q) (even if JAK2 is mutated) [1] - these should be classified as MDS with isolated del(5q).

Genomic Gain/Loss/LOH

One study identified very few recurrent gains and losses below the level of cytogenetic detection [4].

Gene Mutations (SNV/INDEL)

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 [4].

No mutations are specific for any MDS/MPN, including MDS/MPN-U [4].

The WHO in 2017 [1] 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:

*Frequencies from Figure 1 in [3] 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 [4]:

(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 [1].

If a SF3B1 mutation is present, consider whether it is MDS/MPN-RS-T or progression from MDS with ring sideroblasts [1].

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 [1].

There is a significant likelihood of AML developing if there is ASXL1 and SRSF2 co-mutation [3].

Epigenomics (Methylation)

Not known

Genes and Main Pathways Involved

  • Major drivers / early mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SRSF2) [3] [4]
  • Secondary mutations in signaling pathway genes (JAK2) [4]

Diagnostic Testing Methods

  • Bone marrow aspirate
  • Full blood count
  • Cytogenetics

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Prognosis is variable and not well documented [1]
  • There are few data regarding an appropriate prognostic scoring system [1], but IPSS-R [3]or IPSS [8] have been prognostically useful
  • Median overall survival (OS) from various reports: 80 months [4]; 21.8 months [7]; 12 months [3]
  • Leukaemia-free survival: 18.9 months [7]; 10.8 months [3]
  • Leukaemic transformation: 10% [4]; 16% after a median of 10.8 months [3]
    • ASXL1/SRSF2 co-mutation is a significant risk factor [3]
  • Abnormal karyotype associated with inferior OS [4]
  • ASXL1, EZH2, STAG2 mutations associated with shorter OS [3][4]
  • Targeted sequencing may be useful for assessing prognostic impact and making clinical decisions [4].
    • Molecular classification into sub-categories had the strongest prognostic impact in a study by Palomo et al. [4]:
      • 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 [1].

Familial Forms

Not known

Other Information

Refractory anemia with ring sideroblasts and thrombosis (RARS-T) fell within this category prior to the 2016 WHO edition [1][14] but now forms a distinct category, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).


Put your links here (use "Link" icon at top of page)


  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 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.
  2. 2.0 2.1 2.2 2.3 2.4 Ti, Mughal; et al. (2015). "An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms". doi:10.3324/haematol.2014.114660. PMC 4800699. PMID 26341525.CS1 maint: PMC format (link)
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 3.29 P, Bose; et al. (2018). "Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable". doi:10.1182/blood-2018-05-848473. PMC 6236463. PMID 30242087.CS1 maint: PMC format (link)
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 4.29 4.30 4.31 4.32 4.33 4.34 4.35 4.36 4.37 4.38 4.39 4.40 L, Palomo; et al. (2020). "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms". PMID 32573691 Check |pmid= value (help).
  5. L, Cannella; et al. (2008). "Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification". PMID 17709138.
  6. M, Meggendorfer; et al. (2018). "The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms". doi:10.3324/haematol.2017.183160. PMC 5927999. PMID 29700173.CS1 maint: PMC format (link)
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Sa, Wang; et al. (2014). "Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms". doi:10.1182/blood-2014-02-553800. PMC 4067498. PMID 24627528.CS1 maint: PMC format (link)
  8. 8.0 8.1 8.2 8.3 Cd, DiNardo; et al. (2014). "Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy". doi:10.1038/leu.2014.8. PMC 3981947. PMID 24492324.CS1 maint: PMC format (link)
  9. Barbouti, Aikaterini; et al. (2004). "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". The American Journal of Human Genetics. 74 (1): 1–10. doi:10.1086/380648. PMC 1181896. PMID 14666446.CS1 maint: PMC format (link)
  10. T, Fioretos; et al. (1999). "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". PMID 10381517.
  11. R, Kanagal-Shamanna; et al. (2012). "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". PMID 22038701.
  12. McClure, R. F.; et al. (1999). "Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course". British Journal of Haematology. 106 (2): 445–454. doi:10.1046/j.1365-2141.1999.01537.x. ISSN 0007-1048.
  13. 13.0 13.1 M, Meggendorfer; et al. (2013). "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". PMID 23628959.
  14. A, Orazi; et al. (2008). "The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features". PMID 18480833.


*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.