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.

• Authors: A de Laurentiis, J Hiscott, M Alcalay
• Journal: Oncogene (Oncogene) Vol. 34 Issue 49 Pg. 6018-28 (Dec 03 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25893288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• IRF3 protein, human
• Interferon Regulatory Factor-3
• Interleukin-7
• Oncogene Proteins, Fusion
• TEL-AML1 fusion protein

Topics

• Animals
• B-Lymphocytes (physiology)
• Cell Differentiation
• Cell Line, Tumor
• Cells, Cultured
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• Humans
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Interleukin-7 (pharmacology)
• Mice
• Oncogene Proteins, Fusion (genetics, metabolism)
• Phosphorylation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Signal Transduction