Recent advances in understanding myelofibrosis and essential thrombocythemia

Abstract

The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery of CALR mutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient's constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the development of JAK2 inhibitors.

Keywords: Myeloprolifarative neoplasms; myelofibrosis; thrombocythemia.

Figure 1.. Calreticulin (CALR) and CALR mutation in essential thrombocythemia (ET) and myelofibrosis (MF).

( a) CALR protein structure. CALR includes different domains responsible for the two major activities (chaperone and calcium buffering). The mutations lead to altered C-terminal part with loss of KDEL (retrieval and retention domain in endoplasmic reticulum) and generation of a new tail with low calcium-buffering activity. ( b) Progression from ET to MF with CALR mutants. CALRdel52 induces ET always progressing to MF in mice in contrast to CALRins5. Thus, in vivo modeling of CALRdel52-induced pathologic effects induces a disorder characterized by a continuum between ET and MF. ( c) Pie chart of the different CALR mutations in patients with ET and MF.

Figure 2.. Role of microenvironment in the development of myelofibrosis

Mutated dysplastic megakaryocytes (MKs) are responsible for the myelofibrosis and osteoclerosis by inducing the release of (i) non-activated transforming growth factor β1 (TGFβ1), which is activated in the bone marrow environment by a so far uncharacterized mechanism, possibly via integrins and matrix such as fibronectin and thrombospondin (TSP). Fibrosis begins around MKs associated with the proliferation of fibroblasts and eventually osteoblasts, (ii) interleukin-1α (IL-1α) is released and induces osteoprotegerin (OPG) by t stromal cells, a decoy receptor that blocks osteoclast production. Mutated hematopoietic stem cells (HSCs) induce the increase in IL-1α and the subsequent degradation of Schwann cells and mesenchymal stem cells, leading to fibrosis and osteosclerosis through cytokine storm and providing a favorable environment for the hematopoietic clone.

Figure 3.. The type and the number of mutations determine the phenotype of the disease

Boundaries between diseases are not easy to determine and could be dependent on the types or the number of mutations. Proliferation is driven mainly by signaling mutations ( JAK2, CALR, and MPL) while most of the mutations in epigenetic regulators and spliceosome components lead to differentiation defects. Thus, it can be considered that primary myelofibrosis (PMF) is not a pure myeloproliferative neoplasm (MPN) but a disorder with both myeloproliferative and myelodysplastic components. The heterogeneity of the disease and its prognosis are dependent on the respective levels of each component, and prognosis is poor if myelodysplastic features are predominant.