Functional characterisation of SLC2A3 and PFKP in t(8;21)-positive acute myeloid leukemia

The translocation t(8;21) is the most prevalent chromosomal rearrangement in acute myeloid leukaemia (AML) and results in the expression of the oncogenic fusion protein RUNX1/ETO. The fusion protein is required for maintaining the leukaemic phenotype. Previous in vivo work identified genes related to glycolysis, namely SLC2A3 and PFKP as potential transcriptional targets for RUNX1/ETO. This project aimed to functionally investigate the role of SLC2A3 and PFKP in RUNX1/ETO-driven leukaemia both in vivo and in vitro. SLC2A3 significantly maintained the fitness of leukaemic cells under limited glucose and hypoxic conditions in the RUNX1/ETO-expressing Kasumi-1 cell line. Notably, SLC2A3 knockdown impaired the competitive fitness of patient-derived xenograft (PDX) cells in high glucose and oxygen condition. Furthermore, PFKP knockdown results in loss of populations both in vitro and in vivo. Besides, double knockdown of SLC2A3 and PFKP caused G1 cell cycle arrest and had a greater effect in impairing leukaemic cell propagation and fitness when compared to the single knockdowns. Moreover, RUNX1/ETO-expressing cells showed to have a high sensitivity towards 2- deoxyglucose (2DG). 2DG is an analogue of glucose molecule that blocks glycolysis upstream of PFKP. RUNX1/ETO cells treated with this inhibitor undergo apoptosis associated with the overall decrease in cell number. The combination of 2DG and cell cycle inhibitor, palbociclib led to an additive effect and severely impaired expressions of genes in the glycolysis pathway. Collectively, the oncogenic fusion protein, RUNX1/ETO shows dependency on glycolysis through SLC2A3 and PFKP. Targeting these two genes may instruct new treatment strategies with reduced toxicity in t(8;21) leukaemia

Molecular Cytogenetics Of Myelodysplastic Syndrome – Hospital Based Study

Myelodysplastic Syndrome (MDS) is a haematological condition characterised by hypercellular bone marrow and low peripheral blood counts. The objectives of this study were to identify chromosomal aberration using conventional cytogenetics and array comparative genomic hybridisation (array-CGH) in MDS patients and correlate with its’ haematological findings. A total of 8 patients were recruited. Cytogenetic mresults revealed six normal karyotypes, a karyotype with structural abnormalities (del(5)(q13q33) and a karyotype with complex rearrangement (t(1;11), t(2;11), del(4p), del(5p), del(9p)). By array-CGH technique, known cytogenetic aberrations, complex chromosome aberrations and rare/cryptic aberrations (<5 Mb) were detected

The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML