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. 2012 Dec;29(4):2388-95.
doi: 10.1007/s12032-012-0202-3. Epub 2012 Mar 15.

Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy

Jacek Treliński  1 , Krzysztof Chojnowski, Barbara Cebula-Obrzut, Piotr Smolewski
Affiliations

Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy

Jacek Treliński et al. Med Oncol. 2012 Dec.

Abstract

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p=<0.05 and p<0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p=0.02 and p=0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET.

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Figures

Fig. 1
Fig. 1
a Cytometric assessment of megakaryocytes (MKCs) based on forward scatter (FSC) versus side scatter (SSC) distribution. For excluding of monocyte-platelet and granulocyte-platelet conjugates, staining for CD42b, CD14 and CD11b was performed. MKCs were detected in FSChigh/SSChigh population. b Detection of apoptosis parameters (Annexin-V, Caspase 3) on MKCs determined as FSChigh/SSChigh/CD42b+/CD14-/CD11b- cells
Fig. 2
Fig. 2
Detection of apoptosis parameters (Annexin-V, Caspase 3) on bone marrow mononuclear cells (BMMCs). BMMCs were defined based on FSC versus SSC distribution
See this image and copyright information in PMC

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