Sundaresh, A; (2016) Aberrant transcriptional pathways in t(12;21) Acute Lymphoblastic Leukaemia. Doctoral thesis , UCL (University College London).

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Abstract

The single most frequent chromosomal translocation associated with childhood Acute Lymphoblastic Leukaemia is the t(12;21) rearrangement, that creates a fusion gene between TEL (ETV6) and AML1 (RUNX1). Although TELAML1+ patients have a very good prognosis, relapses occur in up to 20% of cases and many patients face long-term side effects of chemotherapy. Our laboratory has previously shown that TEL-AML1 regulates Signal Transducer and Activator of Transcription 3 (STAT3) activation, which is critical for survival of the leukaemic cells. In this study, inhibition of STAT3 in TEL-AML1+ cells results in decreased SMAD7 gene expression. SMAD7 is an antagonist of TGF-β signalling, functioning through a negative feedback mechanism, but is also known to function in other biological pathways. In order to investigate the role of SMAD7 in TEL-AML1+ leukaemia, lentiviral mediated SMAD7 knockdown was performed in human TELAML1+ cell lines. SMAD7 silencing inhibited proliferation of TEL-AML1+ cell lines, eventually leading to growth arrest and apoptosis. Furthermore, our data showed that this effect is not mediated through TGF-β signalling, indicating that SMAD7 was functioning through an alternative pathway. We also observed growth arrest following SMAD7 knockdown in other ALL and AML subtypes. Furthermore, silencing of SMAD7 in TEL-AML1+ ALL cells transplanted into immunodeficient mice impaired disease progression in vivo, resulting in prolonged disease latency. To investigate the essential pathways regulated by SMAD7 in these leukaemic cells, we performed RNA-sequencing analysis on TEL-AML1+ cells following SMAD7 knockdown. Global gene expression analysis revealed SMAD7 to be a regulator of cholesterol biosynthesis, a pathway critical for leukaemia cell survival. Our 4 experiments establish a novel transcriptional pathway operating specifically in t(21;21) ALL, but regulating downstream pathways essential for ALL in general. This study highlights new therapeutic opportunities for ALL.

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