The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.
Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR͞SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.t(8;21) ͉ truncated protein ͉ hematopoietic malignancy ͉ mouse model ͉ cell cycle C hromosomal translocations involving transcriptional regulators and͞or signaling molecules are a common theme associated with dysregulation of hematopoiesis. The transcription factor AML1 (Acute Myeloid Leukemia 1, also called RUNX1, CBF␣, and PEBP2␣B) and its heterodimerization partner CBF are frequent targets of genetic alterations or chromosomal translocations in leukemia (1-3). A common AML1 involved chromosomal translocation, t(8;21)(q22;q22), is found in 12% of all acute myeloid leukemia (AML) cases, including 40-50% of AML M2 subtype and a small portion of M0, M1, and M4 subtypes [French-American-British (FAB) classification] (4-7). The translocation brings together the DNA sequence encoding the N terminus of the AML1 with nearly all of ETO (eighttwenty-one; also called MTG8 and CBFA2T1) to generate the fusion protein AML1-ETO (8-11). AML1-ETO-involved leukemogenesis provides a challenging and excellent model to study cell proliferation and differentiation.A critical step toward understanding many human pathological processes is to produce the human disease in animal models. Several of the mouse models of AML1-ETO expression that have been developed over the years have shown limited success in reproducing and dissecting molecular mechanisms of t(8;21)-associated AML development. Heterozygous AML1-ETO knockin mice (12, 13) died at the embryonic stage of embryonic day 12.5 (E12.5)-E13.5, failing to establish definitive hematopoiesis. Various subsequent transgenic mouse models that circumvented embryonic lethality did not develop any malignancies (14-16), indicating that AML1-ETO alone was not sufficient for leukemia development. Furthermore, by using retroviralmediated AML1-ETO expression and bone marrow transplantation, AML1-ETO alone did not induce AML (17-19). However, treatment of MRP8-AML1-ETO transgenic mice (15)...
The 8;21 translocation is a common chromosomal abnormality in acute myeloid leukemia (AML). We recently identified a naturally occurring leukemogenic splice variant, AML1-ETO9a (acute myeloid leukemia-1 transcription factor and the eighttwenty-one corepressor-9a), of t(8;21). To understand the leukemic potential of AML1-ETO9a, we performed microarray analysis with the murine multipotential hematopoietic FDCPmix A4 cell line. We identified changes in expression of various genes including CD44. CD44 is a type I transmembrane protein and functions as the major cellular adhesion molecule for hyaluronic acid, a component of the extracellular matrix. CD44 is expressed in most human cell types and is implicated in myeloid leukemia pathogenesis. We show that the presence of AML1-ETO9a significantly increased the expression of CD44 at both RNA and protein levels. Furthermore, the CD44 promoter is bound by AML1-ETO9a and AML1-ETO at the chromatin level. In addition, in the AML1-ETO9a leukemia mouse model CD44 is regulated in a cell context-dependent manner. Thus, our observations suggest that AML1-ETO and its splice variant AML1-ETO9a are able to regulate the expression of the CD44 gene, linking the 8;21 translocation to the regulation of a cell adhesion molecule that is involved in the growth and maintenance of the AML blast/stem cells.
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