Aberrant transcriptional pathways in t(12;21) Acute Lymphoblastic Leukemia

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 TEL-AML1 + 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 TEL-AML1 + 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

Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

“…First of all, E/R can reduce sensitivity to the inhibition of proliferation mediated by TGF-β signaling, suggesting that the dysregulated immune responses to infection might promote the malignant evolution of pre-leukemic clones [ 70 ]. The E/R fusion gene can also induce signal transducer and activator of transcription 3 ( STAT3 ) activation, aiding to the self-renewal and leukemogenic activity of leukemia cells [ 77 , 78 ]. STAT3 activation has been shown to transcriptionally induce MYC [ 77 ] and SMAD7 [ 78 ] gene expression in E/R leukemic cells.…”

“…The E/R fusion gene can also induce signal transducer and activator of transcription 3 ( STAT3 ) activation, aiding to the self-renewal and leukemogenic activity of leukemia cells [ 77 , 78 ]. STAT3 activation has been shown to transcriptionally induce MYC [ 77 ] and SMAD7 [ 78 ] gene expression in E/R leukemic cells. In addition, the E/R gene product can activate the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway [ 79 ], resulting in proliferation and cell survival of leukemic cells.…”