Reprogramming Leukemia Cells to Terminal Differentiation and Growth Arrest by RNA Interference of PU.1

Papetti, Michael; Skoultchi, Arthur I.

doi:10.1158/1541-7786.mcr-07-0145

Cited by 21 publications

(23 citation statements)

References 48 publications

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“…These findings collectively show that manipulating the relative expression of transcription factor levels (for example, inhibition of GATA-1 or activation of PU.1 (or vice versa), in erythroleukemias may represent an efficient tool for inducing, and rescuing, leukemic blasts cells into a differentiated cell state. 6,91 In summary, regulation of both PU.1 and GATA-1 expression levels are crucial for the correct cell fate determination of multipotential progenitors and that inappropriate regulation of these primary determinants can cause a block of cell differentiation and expansion of a clonal population of leukemic cells. The developmental block seems to occur at the differentiation stage where primary determinants are beginning to specify a cell fate lineage by activating key target transcription factors.…”

Section: Gata-1 and Pu1 Levels Are Determinants Of Leukemogenesismentioning

confidence: 99%

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

2010

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Hematopoiesis is coordinated by a complex regulatory network of transcription factors and among them PU.1 (Spi1, Sfpi1) represents a key molecule. This review summarizes the indispensable requirement of PU.1 during hematopoietic cell fate decisions and how the function of PU.1 can be modulated by protein-protein interactions with additional factors. The mutual negative regulation between PU.1 and GATA-1 is detailed within the context of normal and leukemogenic hematopoiesis and the concept of 'differentiation therapy' to restore normal cellular differentiation of leukemic cells is discussed.

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Section: Gata-1 and Pu1 Levels Are Determinants Of Leukemogenesismentioning

confidence: 99%

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

2010

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“…Removal of PU.1 (17) or addition of GATA-1 (18) causes erythroid differentiation of MEL cells, the incompleteness of which, however, suggests an involvement of additional factors. In MEL cells, PU.1 physically interacts with GATA-1 (19–21) and silences the transcription of its target genes by creating a repressive chromatin structure (22, 23) that forms when PU.1 binding on GATA-1 involves deacetylation of histone H3 lysine 9 (H3K9) and its trimethylation (22, 23).…”

Section: Introductionmentioning

confidence: 99%

PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation

Burda

Curik

Kokavec

et al. 2009

Molecular Cancer Research

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Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (downregulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein α (Cebpa) and core-binding factor, β subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1.

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“…However, evidence exists to indicate that protein molecules and RNA transcripts are involved to drive cells into commitment state of differentiation [Housman et al, 1980;Tsiftsoglou et al, 2003a]. Moreover, recent experimental data show that alteration in the intracellular level of PU.1 transcription factor via RNAimediated silencing has driven MEL cells into erythroid maturation and growth arrest [Papetti and Skoultch, 2007]. These observations taken together with the data presented in this study indicate that RPS5 transcripts and maybe RPS5 protein are somehow implicated in the initiation of differentiation, since deregulation of both alters the onset of MEL cell erythroid differentiation and the entrance of cells into cell cycle arrest.…”

mentioning

confidence: 99%

The potential role of ribosomal protein S5 on cell cycle arrest and initiation of murine erythroleukemia cell differentiation

Matragkou

Papachristou

Tezias

et al. 2008

J of Cellular Biochemistry

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Evidence now exists to indicate that some ribosomal proteins besides being structural components of the ribosomal subunits are involved in the regulation of cell differentiation and apoptosis. As we have shown earlier, initiation of erythroid differentiation of murine erythroleukemia (MEL) cells is associated with transcriptional inactivation of genes encoding ribosomal RNAs and ribosomal proteins S5 (RPS5) and L35a. In this study, we extended these observations and investigated whether transfection of MEL cells with RPS5 cDNA affects the onset of initiation of erythroid maturation and their entrance in cell cycle arrest. Stably transfected MEL cloned cells (MEL-C14 and MEL-C56) were established and assessed for their capacity to produce RPS5 RNA transcript and its translated product. The impact of RPS5 cDNA transfection on the RPS5 gene expression patterns and the accumulation of RPS5 protein in inducible transfected MEL cells were correlated with their ability to: (a) initiate differentiation, (b) enter cell cycle arrest at G(1)/G(0) phase, and (c) modulate the level of cyclin-dependent kinases CDK2, CDK4, and CDK6. The data presented indicate that deregulation of RPS5 gene expression (constitutive expression) affects RPS5 protein level and delays both the onset of initiation of erythroid maturation and entrance in cell cycle arrest in inducer-treated MEL cells.

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Reprogramming Leukemia Cells to Terminal Differentiation and Growth Arrest by RNA Interference of PU.1

Cited by 21 publications

References 48 publications

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation

The potential role of ribosomal protein S5 on cell cycle arrest and initiation of murine erythroleukemia cell differentiation

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