Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

Abstract

Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…In recent years, investigation on MPNs revealed that there are three driver mutations (JAK2, MPL and CALR) essential as clonal markers, activating the cytokine receptor JAK2 signaling pathway and the downstream effectors (30,57).…”

“…Although JAK2 V617F homozygous subclones are present in PV and ET patients, the expansion of a dominant homozygous subclone occurs almost exclusively in PV patients (~80% in PV and 50% in ET) (33,57), due to either additional genetic or epigenetic events or non-cell-autonomous selective pressures, such as low levels of circulating erythropoietin in the context of elevated hematocrit (33).…”

“…Besides mutations and other molecular abnormalities, various factors, such as gene burden and individual genetic background, may influence the predisposition for developing an MPN, as well as their heterogeneity (16,57). Although JAK2 V617F homozygous subclones are present in PV and ET patients, the expansion of a dominant homozygous subclone occurs almost exclusively in PV patients (~80% in PV and 50% in ET) (33,57), due to either additional genetic or epigenetic events or non-cell-autonomous selective pressures, such as low levels of circulating erythropoietin in the context of elevated hematocrit (33).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…The CALRETICULIN ( CALR ) driver mutation was identified in approximately 73% of JAK2/MPL mutation-negative ET and MF patients [23]. Mutations occur in exon 9 of CALR in the majority of JAK2 wild-type MPN cases.…”

“…Interestingly, and very reminiscent, STAT5 activation at the ER–Golgi was also described in Flt3-ITD + or KIT D816V + AML cases. Analysis of patient data suggests that CALR mutation-positive patients have a more favorable clinical outcome than patients with JAK2 or MPL mutation-positive MPNs due to a lower risk of thrombosis [23]. …”