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.
SUMMARY It has been suspected that cell cycle progression might be functionally coupled with RNA processing. However, little is known about the role of the precise splicing control in cell cycle progression. Here, we report that SON, a large Ser/Arg (SR)-related protein, is a splicing co-factor contributing to efficient splicing of cell cycle regulators. Down-regulation of SON leads to severe impairment of spindle pole separation, microtubule dynamics, and genome integrity. These molecular defects result from inadequate RNA splicing of a specific set of cell cycle-related genes that possess weak splice sites. Furthermore, we show that SON facilitates the interaction of SR proteins with RNA polymerase II and other key spliceosome components, suggesting its function in efficient co-transcriptional RNA processing. These results reveal a mechanism for controlling cell cycle progression through SON-dependent constitutive splicing at suboptimal splice sites, with strong implications for its role in cancer and other human diseases.
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)...
Defining the ability of simian virus 40 (SV40) to transform human cells has become of even greater importance with the increased understanding that this virus may play a role in some human malignancies. This report documents the requirement for viral small-t (ST) antigen in large-T (LT)-driven transformation of primary fibroblasts, a requirement that cannot be met by a well-known oncogene, c-Ha-ras (EJ-ras), which can cooperate with LT in rodent systems. The cellular gene telomerase is not essential for transformation, although transformed clones are not immortal without it. Similarly, an immortal mesothelial cell line has been developed using LT and telomerase. Immortalized mesothelial cells are morphologically normal, but can be transformed by introduction of ST, or ST + ras, but not by ras alone. It is likely that ST will be required along with LT for transformation of most human cell types.
IntroductionAcute myeloid leukemia (AML) is a heterogeneous disease that is classified based on the presence of specific cytogenetic abnormalities as well as the French-American-British (FAB) classification of the leukemic cells and immunophenotype. One of the common translocations identified in leukemia is between chromosome 8q22 and chromosome 21q22 ( Figure 1a). 1 It is associated with nearly 40% of cases of FAB-M2 AML and 8% to 20% of all cases of AML depending on the genetic background and geographic location of the population. The (8;21) translocation is also observed in approximately 6% of AML M1 and, more rarely, in AML M0, M4, M5, and other myeloproliferative syndromes. 2,3 The involved genes are, on chromosome 8, MTG8 or ETO, meaning myeloid translocation gene or eight twenty-one, respectively, 4,5 and AML1 (acute myeloid leukemia factor 1) on chromosome 21. 4 The commonly used name for the t(8;21) fusion protein is AML1-MTG8 or AML1-ETO, and we refer to it as AML1-ETO in this review. AML1 was also discovered from other studies that are not related to t(8;21) and has several different names. 6 Its HUGO (Nomenclature Committee of the Human Genome Organization) name is RUNX1. In correlation, MTG8/ETO is named RUNX1T1 for RUNX1 translocation 1.The t(8;21) generates the 2 fusion genes AML1-ETO and ETO-AML1 ( Figure 1B). AML1-ETO mRNA is easily detectable using polymerase chain reaction (PCR) primers on 2 sides of the fusion point. However, ETO-AML1 mRNA was not identified using a similar approach (E. Kanbe, D.-E.Z., unpublished data, February 2003). This result indicates that the ETO-AML1 transcript is not expressed, is expressed at an extremely low level, or is highly unstable due to degradation. All of the studies on t(8;21) have therefore focused on AML1-ETO.Most of the coding region of the ETO gene is fused to the AML1 amino terminus containing the DNA-binding runt homology domain (RHD) to generate an AML1-ETO fusion protein ( Figure 1C). 4,5,7 The ETO gene has 14 exons. The original cloned AML1-ETO cDNA contained ETO exons 2 through 11; the fusion transcript produces an AML1-ETO protein of 752 amino acids ( Figure 1C). 8 The ETO portion of the full-length AML1-ETO protein contains 3 proline-serine-threonine (PST)-rich regions and 4 Nervy homology regions (NHR1-4) ( Figure 1C). 9 The PST-rich regions have multiple potential kinase phosphorylation sites (SP [Serine-Proline] and TP [Threonine-Proline]). Phosphorylation of ETO has been reported although no kinase involved in its phosphorylation has been identified. 10 NHR1, also called the TAF (TATA box binding protein associated factor) homology domain, shares a sequence similarity with TAF110 and other related TAFs. NHR2 has a hydrophobic amino acid heptad repeat, which is critical for ETO oligomerization. 11 NHR3 contains a predicted coiled-coil structure. NHR4 is a myeloid-Nervy-DEAF1 (MYND) homology domain with 2 predicted zinc finger motifs.Expression of the AML1-ETO fusion gene is under the control of the AML1 promoter. The AML1 gene has 2 promot...
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