- •Phenotypic driver mutations in JAK2, calreticulin, and MPL are present in 85% to 90% of myeloproliferative neoplasms and induce constitutive activation of JAK2-STAT signaling.
- •Modern sequencing efforts have revealed large parts of the genomic landscape of myeloproliferative neoplasms with additional genetic alterations mainly in epigenetic modifiers and splicing factors.
- •Genetic alterations in myeloproliferative neoplasms are subject to clonal evolution as myeloproliferative neoplasms progress, with high molecular risk mutations impacting dynamics and outcome.
- •Because JAK2 V617F is not specific to myeloproliferative neoplasms and is seen in other myeloid malignancies, it is important to note JAK2 V617F is recurrently detected in clonal hematopoiesis of indeterminate potential.
- •The expanding insight into the genetic basis has facilitated diagnosis and prognostication of myeloproliferative neoplasms and poses novel candidates for targeted therapeutic intervention.
Somatic driver mutations mediating constitutive JAK2-STAT activation
|Mutation||Frequency (%)||Molecular Function|
|95||50–60||50–60||Non–receptor tyrosine kinase mediating hematopoietic cytokine signaling|
|CALR||exon 9||<1||26||18–32||ER chaperone protein interacting with thrombopoietin receptor MPL|
|MPL||exon 10||<1||4||5–9||Thrombopoietin receptor|
Somatic mutations in genes broadly affected in myeloid malignancies
|Class||Mutated Gene||Frequency (%)||Molecular Function|
|Epigenetic regulation||DNMT3A||2–7||0–9||3–15||De novo DNA methylase|
|IDH1/2||2||1||0–6||Isocitrate dehydrogenase generating 2-HG|
|ASXL1||3–12||1–11||13–37||Chromatin remodeling as Polycomb group protein|
|EZH2||0–3||1–3||1–9||PRC2 complex H3K27me3 methyltransferase|
|SUZ12||2–3||<1||2||PRC2 complex component|
|Messenger RNA splicing||SRSF2||3||2||8–18||Serine/arginine-rich splicing factor|
|SF3B1||3||5||6–10||Splicing factor 3B protein complex subunit 1|
|Signaling||N/KRAS||0–1||<1||3–4||Small GTPase activating MAPK pathway signaling|
|CBL||1||1||4–7||E3 ubiquitin-protein ligase regulating JAK2|
|SH2B3 (LNK)||9||3||3–6||Adaptor regulating hematopoietic signaling incl. JAK2|
|PTPN11||<1||0–2||0–2||Protein tyrosine phosphatase dephosphorylating RAS|
|Transcriptional regulation||RUNX1||0–2||0–2||3–4||Transcription factor involved in differentiation of hematopoietic stem cells|
|NFE2||2–3||<1||0–3||Transcription factor involved in myelopoiesis|
|DNA repair||TP53||1||2–6||1||Transcription factor, cell cycle regulator|
|PPM1D||1||2||1||Regulatory inhibitor of TP53|
- Pastore F.
- Bhagwat N.
- Pastore A.
- et al.
High Molecular Risk Mutations and Blast Phase Myeloproliferative Neoplasms
Germline genetic factors involved in myeloproliferative neoplasms
- Bellanné-Chantelot C.
- Rabadan Moraes G.
- Schmaltz-Panneau B.
- et al.
Somatic driver mutations of myeloproliferative neoplasms in clonal hematopoiesis
Clinical significance of genetic markers in myeloproliferative neoplasms
Significance of Genetics for Diagnosis of Myeloproliferative Neoplasms
|Blood (m/f)||Platelet count >450 × 109/L||No specific requirement (cytoses or cytopenias possible)||No specific requirement (cytoses or cytopenias possible)|
The Significance of Genetics for Prognostication in Myeloproliferative Neoplasms
|Driver mutations||CALR type 1/like mutation absent||1||CALR type 1/like mutation absent||1||CALR mutation absent||2|
|Hemoglobin <100 g/L|
WBC >25 × 109/L
Platelets <100 × 109/l
Peripheral blood blasts ≥2%
Fibrosis ≥ grade 2
|Hemoglobin <110 g/L|
Platelets <150 × 109/l
Peripheral blood blasts ≥3%
Age at diagnosis 40–90 y
|Risk category (points)||Low|
Significance of Genetics for Myeloproliferative Neoplasm Therapy
- Pastore F.
- Bhagwat N.
- Pastore A.
- et al.
Clinics care points
- •JAK2, CALR, and MPL mutations are present in approximately 98% of patients with PV and 85% to 90% of patients with ET and patients with PMF and represent a mainstay for diagnosis of MPN according to World Health Organization criteria.
- •In triple-negative MPN, evaluation for ASXL1, EZH2, TET2, IDH1/2, SRSF2, and SF3B1 mutations can assist to determine the clonal nature of the disease.
- •Although CALR mutations associate with favorable prognosis in patients with ET and patients with PMF, the presence of high molecular risk mutations, including ASXL1, EZH2, IDH1,/2 and SRSF2, relate to an unfavorable prognosis in MPN.
- •Genetic factors are increasingly implemented in modern prognostication schemes, including the genetically inspired IPSS, Molecular IPSS7, and Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model scores or novel personalized prediction tools (https://cancer.sanger.ac.uk/mpn-multistage).
- •The constitutive activation of JAK-STAT signaling by somatic driver mutations in JAK2, CALR, and MPL provides a rational basis for JAK2 inhibitor therapy in patients with MPN.
- •Novel targeted therapies, either as single agents or in combination with JAK2 inhibitors, are currently being developed to provide improved treatment concepts.
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Conflicts of interest: S.C. Meyer has consulted for and received honoraria from Celgene/BMS.
Funded by: Swiss National Science Foundation and others .
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