Anti-Apoptotic Pathways in Bone Marrow and Megakaryocytes in Myeloproliferative Neoplasia

Objective: Proliferative activity contributes to bone marrow cellularity in myeloproliferative neoplasia (MPN). Megakaryocytes are the most important cells in MPN bone marrow pathology. JAK2(V617F) mutation constitutively activates JAK2, pErk (phosphorylating extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt signaling. Erk is involved in megakaryocyte differentiation, PI3K-Akt inhibits megakaryocyte apoptosis via Bcl-x(L) and two downstream effectors (p70S6k and Bnip3). Immunohistochemic expression of phosphorylated Erk, Akt, p70S6k and Bnip3 was studied along with microvessel density (MVD) in MPN bone marrow and megakaryocytes. Methods: 36 essential thrombocythemia (ET), 25 polycythemia vera and 45 primary myelofibrosis patients were analyzed for pErk, pAkt, Bnip3, p70S6k and MVD expression by immunostaining bone marrow biopsy sections followed by automated image analysis. JAK2(V617F) was analyzed through real-time PCR in blood samples. Results: pErk and pAkt were significantly higher expressed in MPN megakaryocytes, mainly in ET patients, compared to controls. Bnip3 was higher expressed in bone marrow of control patients and in MPN megakaryocytes. Mainly in ET patients, MPN megakaryocytes showed higher p70S6k expression compared to controls. Conclusion: Increased bone marrow cellularity in MPN patients might be influenced by increased pErk, pAkt and decreased Bnip3 expression. A dominant role for megakaryocytes in ET patients was shown. Increased amounts of megakaryocytes in MPN patients can be due to increased pAkt and p70S6k.