Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Chronic myeloid leukaemia (CML) is characterised by the t(9;22)(q34;q11) chromosomal translocation which gives rise to the active tyrosine kinase fusion protein BCRABL, responsible for driving the disease from the haemopoietic stem cell through to mature myeloid cells. The JAK2 pathway is activated in CML through several mechanisms and has effects on numerous transcription factors and cell cycle regulators, making it an attractive additional target for further treatment in CML. Following bioinformatics analysis of microarray data obtained from the literature, we identified a transcriptional regulatory network downstream from JAK2 and generated a linked gene interaction map. The key genes identified control multiple cell functions which could be affected by deregulation of JAK2 signalling. Using Fluidigm technology this network was analysed in CML patient peripheral blood mononuclear cells (PBMNC) and compared to normal PB-MNC by real time PCR. Data was obtained on 29 transcriptional regulation genes, of these 45% were up-regulated including regulators of cell cycle (CDKN1B, CDK1, FOXM1), differentiation and proliferation (TFDP1, EZH2), 10% were down-regulated including regulators of apoptosis (TNFSF10), and 45% were unchanged including HSP90 and PI3K. Treatment of K562 cells using concentrations of JAK2 inhibitors based on IC50 experiments showed concentration dependent reversal in the up-regulated genes (31% for AT9283, 46% for TG101209 and 46% for ruxolitinib treated cells), and in the down-regulated genes (33% for AT9283, 67% for TG101209 and 67% for ruxolitinib treated cells). Preliminary data in CML CD34+ patient samples treated with single agent nilotinib and ruxolitinib or combination followed a similar pattern, but requires further validation. Overall this study has identified an important transcriptional network downstream of activated JAK2 which is altered in CML and can be corrected by JAK2 inhibition.





Publication Date



S47 - S47