The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation

Abstract

The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/β pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/β pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/β was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…Upon TEL-AML1 expression, EML1 cells lost the capacity to differentiate into B-cells and underwent apoptosis. TEL-AML1 expression impaired the activation of IFNa/b signalling pathway in primary murine and human HSPCs with a dramatic inhibition of IRF3 phosphorylation, a member of the IFN-regulatory transcription factor family (de Laurentiis et al, 2015). This finding is consistent with the downregulation of genes involved in IRF3-IFN signalling as shown in gene expression data derived from blasts of ALL patients expressing TEL-AML1 (Linka et al, 2013).…”

“…De Laurentiis et al (2015) generated an experimental model using the murine haematopoietic stem progenitor cell line EML1 expressing the TEL-AML1 fusion protein, and analysed its differentiation and global gene expression properties. Upon TEL-AML1 expression, EML1 cells lost the capacity to differentiate into B-cells and underwent apoptosis.…”

The mirn23a microRNA cluster antagonizes B cell development

“…5C, upper). We induced B cell differentiation by coculturing the EML cells with OP9 stromal cells in the presence of IL-7 and Flt3L for 6 d [42,43]. After 6 d of coculture, stably transduced EML cultures contained ;4.2 million B220 + B cells, whereas MSCV-mirn23a-transduced EML cells contained ,400,000 B220 + B cells ( Fig.…”

Overexpression of TEL-MN1 Fusion Enhances Resistance of HL-60 Cells to Idarubicin

“…As a transcriptional repressor, the TEL (also called ETV6 ) gene at human chromosome 12p13 encodes a member of the ETS family of transcription [5]. The TEL protein, which belongs to a subset of ETS proteins, regulates the development and growth of diverse cell types, particularly those of hematological tissues.…”

“…Genetic manipulation studies in mice indicated that this gene is required for the development and maintenance of bone marrow-based blood cell formation and the vascular network [7]. However, the TEL gene frequently suffers various mutations that leads to an array of potentially lethal cancers, such as hematological malignancies, usually as a result of its fusion with many partner genes, such as 21q22 (TEL-AML1), 5q33 (TEL-PDGFRβ), 9q34 (TEL-ABL), 9p24 (TEL-JAK2), and 3q26 (TEL-EVI1) [5, 8-11]. It has been reported that the TEL gene is the target of the translocation t(12; 22)(p13;q12), which is a recurrent but infrequent chromosome abnormality in human myeloid malignancies [12].…”