Identification of murine CBFα1, a runt domain transcription factor, as a putative Myc collaborator in T cell lymphoma

Neil, James C.; Stewart, Monica; Terry, Anne; O’Hara, Maureen; Hu, Ming; Blyth, Karen; Baxter, Euan W.; Onions, David; Cameron, Ewan R.

doi:10.1038/sj.leu.2401295

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…Runx proteins function as promoter-bound scaffolds that organize the regulatory machinery for gene expression within punctate subnuclear domains during interphase (18,19). Pathological perturbations in the organization of these domains are linked with altered development and tumorigenesis (10,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Temporal and spatial changes of these architecturally organized Runx domains occur during mitosis (13).…”

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confidence: 99%

Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2

Young

Hassan

Yang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

181

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During cell division, cessation of transcription is coupled with mitotic chromosome condensation. A fundamental biological question is how gene expression patterns are retained during mitosis to ensure the phenotype of progeny cells. We suggest that cell fate-determining transcription factors provide an epigenetic mechanism for the retention of gene expression patterns during cell division. Runx proteins are lineage-specific transcription factors that are essential for hematopoietic, neuronal, gastrointestinal, and osteogenic cell fates. Here we show that Runx2 protein is stable during cell division and remains associated with chromosomes during mitosis through sequence-specific DNA binding. Using siRNA-mediated silencing, mitotic cell synchronization, and expression profiling, we identify Runx2-regulated genes that are modulated postmitotically. Novel target genes involved in cell growth and differentiation were validated by chromatin immunoprecipitation. Importantly, we find that during mitosis, when transcription is shut down, Runx2 selectively occupies target gene promoters, and Runx2 deficiency alters mitotic histone modifications. We conclude that Runx proteins have an active role in retaining phenotype during cell division to support lineage-specific control of gene expression in progeny cells.L ineage commitment and cell proliferation are critical for normal tissue development. Preservation of phenotype during clonal expansion of committed cells necessitates the faithful segregation of chromosomes and the conveyance of lineage-specific gene regulatory machinery to progeny cells. Mitosis involves nuclear reorganization, global chromosome condensation, and transcription silencing and occurs concomitant with protein degradation and/or displacement of many regulatory factors from chromosomes (1-4). One fundamental question is how cells are programmed to sustain phenotypic gene expression patterns after cell division when transcriptional competency is restored in progeny cells.Cell fate is determined in response to extracellular cues by lineage-specific master regulators that include the Runx family of transcription factors. In mammals, these proteins are required for development of hematopoietic (Runx1), osteogenic (Runx2), and gastrointestinal and neuronal (Runx3) cell lineages (5-11). Runx factors integrate cell signaling pathways (e.g., TGF-␤/bone morphogenetic protein and Yes/Src) and recruit chromatin-modifying enzymes (e.g., histone deacetylases, histone acetyltransferases, SWI/SNF, SuVar139) to modulate promoter accessibility within a nucleosomal context (10,(12)(13)(14)(15)(16)(17). Runx proteins function as promoter-bound scaffolds that organize the regulatory machinery for gene expression within punctate subnuclear domains during interphase (18,19). Pathological perturbations in the organization of these domains are linked with altered development and tumorigenesis (10,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Temporal and spatial changes of these architecturally organized Runx domains occur during...

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mentioning

confidence: 99%

Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2

Young

Hassan

Yang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

181

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“…In this way, various collaborating oncogenes have been found for Cmyc in T and B cell lymphomagenesis. 65,66 Similar studies should be possible in AML with the advent of promoters suitable for expression in the myeloid compartment.…”

Section: Figurementioning

confidence: 98%

Genetic heterogeneity in acute myeloid leukemia: maximizing information flow from MuLV mutagenesis studies

Largaespada

2000

Leukemia

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The study of myeloid leukemia induced by slow transforming murine leukemia viruses (MuLV) in the laboratory mouse has led to discovery of many important genes with critical roles in regulating the growth, death, lineage determination and development of hematopoietic precursor cells. This review provides an overview of the susceptible strains and virus isolates that cause acute myeloid leukemia (AML) in mice. In addition, newer methodologies, involving the use of the polymerase chain reaction, that have been used to identify cancer genes mutated by proviral insertion in mouse models, will be discussed. As cancer is a multi-gene disease, a system in which pairs of oncogenic mutations are classified as redundant, neutral or synergistic is described. The potential to combine MuLV mutagenesis with recent advances in mouse transgenesis in order to model specific forms of myeloid leukemia or genetic pathways common in human AML will be discussed. Finally, a general strategy for maximizing these genetically rich models to foster a better understanding of AML physiology and developing therapies is proposed. Leukemia (2000) 14, 1174-1184. Keywords: acute myeloid leukemia; mouse; MuLV; molecular cloning MuLV-induced AMLSeveral excellent reviews have been published which describe MuLV-induced leukemia [1][2][3][4][5][6] or mouse models of AML. 7-9Therefore, only a brief summary of the diversity of mouse strains and virus combinations that result in AML is in order. For the purposes of this review, acute erythrocytic and megakaryocytic leukemias are not considered; instead, the focus is on AML representing earlier progenitors or neutrophil and monocyte/macrophage progenitors. It had been shown that various MuLV could induce non-B, non-T cell leukemia in susceptible mice by the early 1980s. [10][11][12][13][14][15] It was shown that these leukemias consisted of cells in various myeloid lineages and stages of maturation. Criteria for classification of myeloid leukemia in mice have included lack of B or T cell antigen receptor gene rearrangements, 16,17 myeloid esterase staining, 11 cell and nuclear morphology, 13,18 induction of differentiation to mature myeloid cell types and expression of lineage-specific genes or cell surface markers. 15,19 A system of classification of human AML into subtypes, called the French-American-British (FAB) system, 20,21 has proved useful in distinguishing AML according to many important clinical phenotypes such as prognosis, response to various therapies, development of intercurrent problems, and Table 1). The FAB subclassifications are based primarily on morphological appearance, myeloid esterase staining, and expression of cell surface markers. To some extent, specific genetic changes, such as chromosomal translocations, tend to cluster within a FAB subtype of AML, indicating that these definitions do indeed reflect basic genetic differences between subtypes that probably dictate their behavior. A good example of this is the strong correlation between translocations involving the retinoic ac...

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“…110,111 In CD2-Runx2 transgenic mice, spontaneous lymphomas developed with low frequency and long latency, but these tumors were accelerated when animals were mated with CD2-c-Myc mice, confirming the synergy between the two proto-oncogenes. 153,154 Runx1 and Runx2 share similar binding sites. 155 Since Runx1 binds to many of the T cell leukemogenic viral enhancers (see above), it is possible that Runx2 overexpression further elevates enhancer activity.…”

Section: How Have Retroviruses Been Useful For Identification Of Genementioning

confidence: 99%

What retroviruses teach us about the involvement of c-Myc in leukemias and lymphomas

et al. 2002

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Identification of murine CBFα1, a runt domain transcription factor, as a putative Myc collaborator in T cell lymphoma

Cited by 5 publications

References 17 publications

Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2

Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2

Genetic heterogeneity in acute myeloid leukemia: maximizing information flow from MuLV mutagenesis studies

What retroviruses teach us about the involvement of c-Myc in leukemias and lymphomas

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