TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis

Perrotti, Danilo; Bonatti, Silvia; Trotta, Rossana; Martinez, Robert V.; Skórski, Tomasz; Salomoni, Paolo; Grassilli, Emanuela; Iozzo, Renato V.; Cooper, Denise R.; Calabretta, Bruno

doi:10.1093/emboj/17.15.4442

Cited by 126 publications

(142 citation statements)

References 57 publications

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“…Such in vitro assays may not re¯ect the direct role of oncogenes in hematopoiesis in vivo. For example, expression of BCR-ABL in 32D cells prevented G-CSF-induced di erentiation (Perrotti et al, 1998) but expression of BCR-ABL in bone marrow cells in mice induces a myeloproliferative disorder without blocking cell di erentiation (Zhang and Ren, 1998). In this report we have shown that expression of AME alone does not block myeloid di erentiation during the 4-month pre-leukemia stage in mice despite causing other impairments in hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

Cuenco

Ren

2001

Oncogene

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The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid di erentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL e ciently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/ MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid di erentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid di erentiation and rapidly induce an AML. Our results suggest that block of myeloid di erentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription. Oncogene (2001) 20, 8236 ± 8248.

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Section: Discussionmentioning

confidence: 99%

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

Cuenco

Ren

2001

Oncogene

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“…It is also known to impact signaling pathways in a specific manner as shown with its specific activation of the MAPK pathway [93]. The phosphorylation of TLS-FUS, a nuclear transcription factor that also functions in splicing, demonstrates the versatility of PKCβII functions [94,95]. The observation that PKCβII acts to phosphorylate Akt on Ser473 and acts as a PDK2 (phosphoinositide dependent kinase type 2) activity [96], underscores the role of PKCβII in signaling pathways.…”

Section: Pkcβiimentioning

confidence: 96%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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“…Bcl-X L , GCSFR, C/EBPa and b, MDM2 and MYC) are aberrantly regulated by increased BCR/ABL expression through the activity of specific mRNA binding proteins (e.g. TLS/FUS, hnRNP A1, hnRNP E2, La, hnRNP K and CUGBP1) (Perrotti et al, 1998;Iervolino et al, 2002;Perrotti et al, 2002;Trotta et al, 2003;Guerzoni et al, 2006;Notari et al, 2006). Specifically, the mRNA export activity of hnRNP A1, an RNAbinding protein overexpressed in CML-BC, is required for cytokine-independent proliferation, survival and tumorigenesis of acute phase CML blasts and BCR/ABL-expressing myeloid progenitor cell lines .…”

Section: Bcr/abl and Pp2a: The Yin And Yang Of Blast Crisis CMLmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis

Cited by 126 publications

References 57 publications

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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