Constitutive tyrosine kinase activity of BCR ABL fusion gene

Constitutive tyrosine kinase activity of BCR/ABL fusion genes causes uncontrolled cell growth and is also thought to be responsible for a variety of changes in normal cellular functions like differentiation, adhesion, migration and apoptotic response in CML. Therefore it is important to know the expression levels of various leptin and adiponectin receptor isoforms in newly diagnosed CML patients and after BCR/ABL suppression by imatinib in terms of the involvement in the pathogenesis of leukemias. The aim of this study was therefore, for elucidating the potential role of leptin and adiponectin receptors expressions in the pathogenesis of CML and in CML cell lines in vitro.
Materials and methods
Results
Discussion In the present study, we first assessed the expression levels of long, short and total leptin receptor isoforms in two CML cell lines. We found that three leptin isoforms are expressed in both cell lines. OB-Rt and OB-Ra levels in Meg-01 1-Oleoyl lysophosphatidic acid sodium salt line were significantly lower than those of K562 cells. Despite their different expression with respect to each other, previous studies reported the expression of OB-Rt, OB-Ra, and OB-Rb in hematopoietic cell lines [12], [13], [22], [23]. The difference in expression of OB-R isoforms in K562 and Meg-01 could be due to different origins of the cell lines, since these cells refer to erythroleukemia and megakaryocytic leukemia, respectively. Despite the well established role of OB-Ra and OB-Rb of inducing various biological functions via different signaling pathways [11], it was also reported that OB-Rb plays a crucial role especially in leptin proliferative activity. However, the proliferative responses of these cell lines were not correlated with level of leptin receptor expression [5], [12]. In this study, the expression of all leptin receptor isoforms when compared to the control group, were found to be down regulated with significantly in CML patients. Meanwhile, the OB-Rb intensity obtained in the control group was found to be undetectably low. Previous studies reported lower expression OB-Rb than OB-Ra in normal PBMC [24]. Another study reported stating the lack of OB-Rb expression and also with OB-Ra expression in low level in normal promyelocytes. In addition, these reports depicted decreased expression of leptin receptor during in vitro differentiation of leukemic cells [12], [13]. The downregulation of three OB-R isoforms in CML patients shows the aberration of OB-R expression and suggests its involvement in normal hematopoiesis. These results also support the previous studies on the role of decreased expression of leptin receptors in myeloid development and differentiation [5], [25]. Although increased serum leptin and OB-R expression levels were found in many cancer types with related obesity [26], there are also reports stating the decrease in serum leptin levels in lymphoid and myeloid malignancies [27], [28], [29]. However, previous studies reported contradictory results upon comparison between serum leptin levels with OB-R receptor levels in myelodysplastic sendrome (MDS), AML and leukopenic patients and controls [12], [28], [30], [31]. This discrepancy creates a difficulty concerning building the correlation between serum leptin level and OB-R receptor expression in CML patients. Leptin and adiponectin are the best known adipokines in hematopoesis, acting in an opposite fashion. It is well known that adiponectin treatment has been lead to suppression of cell proliferation and induction of apoptosis [14], [32], [33]. The earlier studies reported that adiponectin serum levels have been inversely associated with childhood acute myeloblastic leukemia (AML), and with other types of childhood leukemia. Moreover, in both chronic myeloproliferative and lymphoproliferative disorders circulating levels of adiponectin were found to be lower [34]. A recent report has revealed that AdipoRs mRNA is expressed in human lymphocytes [34].