Short answer: Myeloproliferative neoplasms (MPNs: polycythemia vera, essential thrombocythemia and primary myelofibrosis) are clonal diseases of effective, excessive blood cell production that are defined by a driver mutation in JAK2, CALR or MPL plus a characteristic bone marrow picture. Myelodysplastic syndromes (MDS) are clonal diseases of ineffective hematopoiesis, defined by cytopenias, dysplasia and less than 20% blasts, with classification and risk now incorporating genetics such as SF3B1 and TP53. The two major classification systems, the WHO 5th edition and the International Consensus Classification (ICC) 2022, agree on most MPN criteria and differ mainly in how they handle MDS blast thresholds, SF3B1 and TP53.
Author and disclosure: Roupen Odabashian, MD, FRCPC, Oncologist and founder of MeDucation AI. I am the founder of MeDucation AI, which sells hematology and oncology board preparation. I have no other financial relationships relevant to the topics discussed here. This article is educational and is not a substitute for individualized clinical judgment or tumor board discussion.
What is the difference between an MPN and MDS?
MPNs drive overproduction of mature cells (red cells, platelets or both) with a hypercellular marrow and a high frequency of JAK2, CALR or MPL driver mutations. MDS produces cytopenias despite a usually normo or hypercellular marrow because hematopoiesis is ineffective, and it is characterized by dysplasia, recurrent cytogenetic abnormalities and mutations in splicing and epigenetic genes. Overlap diseases exist, including chronic myelomonocytic leukemia (CMML) and MDS/MPN with SF3B1 and thrombocytosis, which is why a clean separation is not always possible and why classification systems treat them as their own group.
How are PV, ET and PMF diagnosed?
Disease | Key diagnostic criteria (2016 WHO, retained in essentials by the 5th edition) |
|---|---|
Polycythemia vera | Hemoglobin above 16.5 g/dL in men or 16.0 g/dL in women, or hematocrit above 49% or 48%; hypercellular marrow with trilineage growth and pleomorphic mature megakaryocytes; JAK2 V617F or JAK2 exon 12 mutation; subnormal serum erythropoietin as the minor criterion. Diagnosis requires all three major criteria, or the first two plus the minor criterion. |
Essential thrombocythemia | Platelets of at least 450 × 10⁹/L; marrow with enlarged, mature, hyperlobulated megakaryocytes and no significant left shift; exclusion of CML, PV, PMF, MDS and other myeloid neoplasms; JAK2, CALR or MPL mutation. Diagnosis requires all four major criteria, or the first three plus a clonal marker or absence of reactive thrombocytosis. |
Primary myelofibrosis | Prefibrotic form: atypical megakaryocyte proliferation with reticulin fibrosis of grade 1 or less. Overt form: megakaryocyte proliferation with grade 2 or 3 reticulin or collagen fibrosis. Both need exclusion of other myeloid neoplasms and a driver mutation or another clonal marker, plus at least one minor criterion (anemia, leukocytosis of at least 11 × 10⁹/L, palpable splenomegaly or raised LDH; leukoerythroblastosis for the overt form). |
The practical board pearl is that the bone marrow biopsy distinguishes ET from prefibrotic myelofibrosis, which have different prognoses despite looking similar on a complete blood count.
How common are the MPN driver mutations?
Mutation | Where it is found |
|---|---|
JAK2 V617F | About 95% of PV; about 60% of ET and PMF |
JAK2 exon 12 | About 3% to 5% of V617F negative PV |
CALR (exon 9 indels) | Type 1 predominates in PMF; type 2 is mainly seen in ET |
MPL (mostly codon 515) | About 4% of ET and 8% of PMF |
Triple negative | Up to 20% of ET and 10% to 15% of PMF |
A triple negative result does not exclude an MPN. Additional mutations such as ASXL1, EZH2, TET2, IDH1 or IDH2, SRSF2 and SF3B1 are found in about half of PMF cases and serve as clonal markers.
How do the WHO 5th edition and the ICC differ for MDS?
Feature | WHO 5th edition | ICC 2022 |
|---|---|---|
Blasts of 10% to 19% | Retains the 20% cutoff between MDS and AML for most diseases | Favors a diagnosis of MDS/AML |
MDS with SF3B1 | SF3B1 mutation, or 15% or more ring sideroblasts if testing is unavailable | SF3B1 variant allele fraction of at least 10%, without multi-hit TP53 or RUNX1 |
TP53 defined MDS | One or more TP53 mutations, with copy loss or copy neutral LOH if only one, and blasts below 20% | Multi-hit TP53, or TP53 VAF above 10% with a complex karyotype; blasts 0% to 9% |
MDS/MPN with SF3B1 and thrombocytosis | Requires at least 15% ring sideroblasts | Requires SF3B1 VAF of at least 10%; ring sideroblasts not required |
Atypical CML | Called MDS/MPN with neutrophilia | Called atypical CML |
Juvenile myelomonocytic leukemia | Classified as an MPN | Placed with pediatric or germline associated disorders |
Both systems keep the same core idea for CMML: persistent monocytosis, blasts below 20%, and exclusion of CML, other MPNs and eosinophilia associated rearrangements. WHO subtypes CMML into myelodysplastic (WBC below 13 × 10⁹/L) and myeloproliferative (WBC of at least 13 × 10⁹/L) forms. Both also use CML, BCR::ABL1 positive, as the name for CML.
How is MDS risk stratified today?
The Molecular International Prognostic Scoring System (IPSS-M), published in NEJM Evidence in 2022, adds mutation data to the clinical and cytogenetic variables used in earlier scores. It was developed on 2,957 patient samples from 24 centers in 13 countries, incorporates 31 genes, and yields six risk categories from very low to very high plus a continuous patient specific score. In the derivation work, 46% of patients were placed in a different risk category than under the previous system, which can change treatment recommendations. A validation cohort of 754 patients from a Japanese consortium supported the findings. For boards, remember that IPSS-M refines, but does not replace, a full clinical assessment, and that TP53 multi-hit disease carries a particularly poor prognosis.
What should you remember for the boards?
JAK2 V617F is nearly universal in PV, so a negative V617F in a patient with erythrocytosis should prompt testing for JAK2 exon 12 and a search for secondary causes.
A normal-looking platelet count with unexplained anemia, leukocytosis, splenomegaly or raised LDH raises the question of prefibrotic myelofibrosis rather than ET.
CALR type 1 is more typical of myelofibrosis, and type 2 more typical of ET.
The MDS to AML boundary differs between WHO (20% blasts for most diseases) and ICC (MDS/AML for 10% to 19%), so read the question stem for which system it uses.
SF3B1 mutated MDS has a more favorable course than TP53 multi-hit MDS, and the genetic definitions in WHO and ICC differ in their thresholds.
To practice this kind of question, see Oncology Board Review Question Banks Compared or the broader plan in How to Pass the ABIM Medical Oncology Boards. For the full exam approach, read Oncology Board Review 2026.
Frequently asked questions
What is the difference between MPN and MDS?
MPNs cause excess production of mature blood cells and are driven by JAK2, CALR or MPL mutations, whereas MDS causes cytopenias through ineffective, dysplastic hematopoiesis with fewer than 20% blasts.
Which mutation is most common in polycythemia vera?
JAK2 V617F, found in about 95% of cases. Most of the remaining cases carry a JAK2 exon 12 mutation.
What is IPSS-M?
The Molecular International Prognostic Scoring System for MDS, which adds mutation data from 31 genes to clinical and cytogenetic variables and gives six risk categories and a continuous score.
How do WHO and ICC differ for MDS?
The main differences are the handling of 10% to 19% blasts (MDS/AML in the ICC), the definition of SF3B1 mutated MDS, and the criteria for TP53 defined disease.
Can an MPN be triple negative?
Yes. Up to 20% of ET and 10% to 15% of myelofibrosis cases lack JAK2, CALR and MPL mutations, and other clonal markers may be used.
References
Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y
Boeckx N. 2022 ICC and 5th WHO classification of hematopoietic neoplasms guidelines: an overview. University Hospitals Leuven. uzleuven.be
Memorial Sloan Kettering Cancer Center. Improved scoring system for myelodysplastic syndromes could help doctors tailor treatment. mskcc.org
Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022. doi:10.1038/s41375-022-01613-1
Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias. Blood. 2022;140(11):1200 to 1228. doi:10.1182/blood.2022015850
Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evid. 2022. doi:10.1056/EVIDoa2200008
