Myeloproliferative neoplasms

The term "myeloproliferative neoplasms" (MPN) (formerly: Chronic Myeloproliferative Diseases - CMPE) is used to describe a group of rare, monoclonal diseases of myeloid stem cells with autonomous proliferation of one or more hematopoietic cell series (leuko,-erytho-, thrombocytosis) .

It belongs to the myeloid neoplasms as well as:

• Mastocytosis
• Myeloid/lymphatic neoplasms with eosinophilia
• Myelodysplastic/ Myeloproliferative Neoplasms
• Acute myeloid leukemia (Arber DA et al 2016; WHO classification).

In addition to clinical presentation, bone marrow morphology, immunophenotype, and cytogenetic findings, advances in molecular characterization, in particular, have contributed to better delineation of the various myeloid diseases. The better knowledge of the pathogenesis and the genetic profile allows a clearer classification of the individual case and, in part, a therapy already targeting the molecular defect.

By definition, the group of MPNs includes the following diseases (WHO 2016)

• Chronicmyeloid leukemia (CML), bcr-abl1 positive
• Chronic neutrophil leukemia (CNL)
• Polycythaemia Vera (PV)
• Primary myelofibrosis (PMF)
• Prefibrotic/early PMF
• Fibrotic ('overt') PMF
• Essential thrombocythaemia (ET)
• Chronic eosinophil leukemia, 'not otherwise specified' (CEL-NOS)
• Myeloproliferative neoplasms, unclassifiable (MPN,U)

Originally, only chronic myeloid leukemia could be clearly diagnosed on the basis of its clonal marker(Philadelphia chromosome or bcr-abl fusion gene) and reliably differentiated from the other MPNs. The detection of acquired driver mutations in the JAK2(Janus kinase), CALR(calreticulin) and MPL (thrombopoietin receptor gene) genes has also made it possible to prove the clonality of ET, PV and PMF and thus to reliably differentiate them from reactive states. However, in contrast to chronic myeloid leukemia, these mutations are not specific for a single MPN subtype. In the diagnostic criteria (WHO 2016) of the rarer entities such as Chronic Neutrophil Leukemia (CNL), Chronic Eosinophil Leukemia, 'not otherwise specified' (CEL-NOS) and Myeloproliferative Neoplasms, Unclassifiable (MPN,U), the detection of a clonal marker has important prognostic and therapeutic relevance. CEL-NOS and MPN,U can usually be diagnosed based on the exclusion of other MPN, could be detected in chronic neutrophil leukemia (CNL) diagnostic applicable 'driver' mutations (point mutations in the 'colony-stimulating factor 3 receptor'; CSFR3 mutations), which are closely associated with CNL (Szuber N et al. (2021).

The relative frequencies of 'driver' mutations in the classic bcr-abl negative MPNs (ET, PV and PMF) can be represented as follows:

• Essential thrombocythemia -Mutated genes: CALR(20-30%); JAK2 (about 60%); MPL (3-5%).
• Polycythaemia Vera -Mutated genes: JAK2 (98%).
• Primary myelofibrosis -Mutated genes: CALR(20-30%); JAK2 (about 60%); MPL (5-8%)

In ET and PMF, 10% to 15% cases have none of the three mutations ('triple negative'), so their definite assignment to MPN can be difficult in some cases. The mutations affect genes of tyrosine kinases that are involved in the regulation of cell proliferation via a common(JAK-STAT) signalling pathway. The respective mutation leads to an autonomous proliferation of one or more cell lines, detached from demand

The JAK2-V617F mutation corresponds to a point mutation in exon 14 of the JAK2 gene. Exclusively in PV (2% - 4%), a mutation in exon 12 of the JAK2 gene was identified. The detected MPL mutations correspond mostly to point mutations localized in codon 515 of the thrombopoietin receptor gene. CALR mutations are several different mutations (insertions/deletions) in exon 9 of the calreticulin gene, the exact localization of which is likely to have a prognostic impact.

Furthermore, it could be shown that in patients with myeloid neoplasia additional somatic mutations (also called non-Driver' or Passenger mutations) can occur. These are mainly mutations in the genes TET2, ASXL1, EZH2, DNMT3A, IDH1/IDH2, SRSF2, TP53. These somatic mutations affect the prognosis of the disease in different ways (Zoi K et al. (2017).

The occurrence of chromosomal aberrations also influences the individual diseases.

Recent molecular studies indicate that the 'driver' mutations can probably be acquired in childhood (possibly even in utero) and that the latency until the onset of MPN can be up to several decades (Williams N et al. (2020)). It remains unclear, for example, how genetic predisposition and acquired mutations interact in the development of MPN and why different disease patterns occur with the same mutation.