Fabien Guidez - Academia.edu (original) (raw)

Papers by Fabien Guidez

Research paper thumbnail of The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

Research paper thumbnail of Additional file 1: of GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

Lists of regulated genes in HR-MDS and AML post MDS relative to FVB/N (Tables S1 to S31). (XLSX 1... more Lists of regulated genes in HR-MDS and AML post MDS relative to FVB/N (Tables S1 to S31). (XLSX 1839 kb)

Research paper thumbnail of Differential DNA binding by PLZF and APL associated RAR alpha-PLZF fusion protein

Research paper thumbnail of BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome

International Journal of Molecular Sciences, 2021

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of... more During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regu...

Research paper thumbnail of Human CREBBP acetyltransferase is impaired by etoposide quinone, an oxidative and leukemogenic metabolite of the anticancer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues

Free Radical Biology and Medicine, 2021

Research paper thumbnail of Efficacy of ABT-737, a BCL-2 Inhibitor, in an NRAS/BCL2 Mouse Model of High Risk Myelodysplasia (HR-MDS) By Targeting Pathways Identified By Gene Expression Profiling

Blood, 2014

Background: MDS lack therapeutic approaches in many instances and very few animal models of MDS a... more Background: MDS lack therapeutic approaches in many instances and very few animal models of MDS available for preclinical testing of new drugs have been reported. We have created transgenic animal models of HR-MDS and acute myelogenous leukemia(AML) post-MDS using mutant NRAS and BCL-2 overexpression (Omidvar Cancer Res.2007;67:1657; Rassool Cancer Res. 2007;67:8762) and reported the efficacy of azacitidine in the HR-MDS model (Gorombei Blood 2013;122:1514) and of the BCL2 inhibitor, ABT-737, on the AML post-MDS model (Beurlet Blood 2013;122:2864). The objective of this study was to determine the effects of this inhibitor on our mouse model of HR-MDS. Methods: The mice were followed for disease and once the platelets fell (<1000x103/mm3) at around 3 months, ABT-737 (75mg/kg) was administered every other day for 15 injections. Responses were measured by survival, peripheral blood (PB) counts and Mac1hi/Gr1lo estimations by flow cytometry (FCM) as a measure of circulating blasts. A...

Research paper thumbnail of Identification of PLZF-Dmrs in Hematopoiesis Highlight a Novel Role of PLZF As a Guardian of Hematopoietic Genome Integrity

Blood, 2014

Background: The eucaryotic genome is organized in chromatin domains which affect its function. Th... more Background: The eucaryotic genome is organized in chromatin domains which affect its function. This organization is partly established by special architectural and transcriptional factors specific to the cellular context. In an hematopoietic context, PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the family of POK repressor proteins, is directly implicated in the regulation of epigenetic modifications by tethering DNA methyltransferases (DNMT) and histone deacetylases (HDAC) to specific genomic targets. We have previously shown that PLZF transcriptional activation is controlled by acetylation of specific lysine residues (K647/650/653) affecting its nuclear localization. PLZF is mainly expressed in CD34 positive cells and has been shown to be crucial in the maintenance of hematopoietic stem cells (HSC). However, the epigenetic role of PLZF in HSC protection and maintenance is not yet understood. Methodology: We created PLZF functional knock-in mouse models by introduc...

Research paper thumbnail of Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia–associated TEL-AML1 oncoprotein

Blood, 2000

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombinat... more The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5′-region of the ETS-related gene, TEL(ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 orPEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruit...

Research paper thumbnail of Benzene-Induced Leukemogenesis: Irreversible Inhibition of PTPN2 and Subsequent STAT1 Signaling Alteration By the Hematotoxic Metabolite Benzoquinone

Blood, 2015

Benzene (BZ) is a chemical compound of industrial and toxicological interest classified as a clas... more Benzene (BZ) is a chemical compound of industrial and toxicological interest classified as a class I human carcinogen. Environmental and occupational exposure to BZ lead to bone marrow malignancies such as leukemia. The leukemogenic effects of BZ relies on its metabolization in bone marrow cells into reactive metabolites, in particular benzoquinone (BQ) that can react with macromolecules (arylation) and/or induce oxidative stress. Although BZ is well recognized as a leukemogenic chemical, most of the key molecular and cellular mechanisms underlying its hematotoxicity are not fully understood. PTPN2 is a protein tyrosine phosphatase (PTP) mainly expressed in hematopoietic cells and playing a key role in the homeostasis of the hematopoietic system. In particular, this PTP is an important modulator of growth factors and JAK/STAT signaling pathways. Loss of function analyses in patients with mutation/deletion of the PTPN2 gene and knock-out mouse models indicate that PTPN2 acts as a tum...

Research paper thumbnail of Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling

Journal of Biological Chemistry, 2019

Research paper thumbnail of T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide

Molecular Pharmacology, 2019

Research paper thumbnail of Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia

Research paper thumbnail of GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

Journal of Hematology & Oncology, 2016

Research paper thumbnail of Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

Nature genetics, Jan 12, 2015

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferati... more Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS an...

Research paper thumbnail of Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases

Epigenetics & chromatin, 2015

The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for t... more The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood. In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity ...

Research paper thumbnail of An acetyltransferase assay for CREB-binding protein based on reverse phase–ultra-fast liquid chromatography of fluorescent histone H3 peptides

Analytical Biochemistry, 2015

Research paper thumbnail of Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression

Cancer research, 2005

Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which d... more Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which dramatically responds to all-trans-retinoic acid (ATRA). Recent studies have indicated that combinatorial use of retinoid and nonretinoid compounds, such as histone deacetylase inhibitors, arsenics, and PKA agonists, has higher therapeutic value in this disease and potentially in other malignancies. In a screen of 370 compounds, we identified benzodithiophene analogues as potent enhancers of ATRA-induced APL cell differentiation. These effects were not associated with changes in global histone acetylation and, for the most potent compounds, were exerted at very low nanomolar concentrations, and were paralleled by enhancement of some, but not all, ATRA-modulated gene expressions. Investigating the mechanism underlying the effects of these drugs on ATRA-induced APL cell differentiation, we have shown that benzodithiophenes enhance ATRA-mediated dissociation and association of corepressor N-...

Research paper thumbnail of The PML-RAR alpha gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells

Oncogene, 1994

Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation ... more Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic ac...

Research paper thumbnail of Role of Nuclear Receptor Corepressors in Leukemogenesis

Current Topics in Microbiology and Immunology, 2001

Research paper thumbnail of Acute Promyelocytic Leukemia: A Paradigm for Differentiation Therapy

Acute Myelogenous Leukemia, 2009

Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation lead... more Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARalpha oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.

Research paper thumbnail of The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3)

Research paper thumbnail of Additional file 1: of GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

Lists of regulated genes in HR-MDS and AML post MDS relative to FVB/N (Tables S1 to S31). (XLSX 1... more Lists of regulated genes in HR-MDS and AML post MDS relative to FVB/N (Tables S1 to S31). (XLSX 1839 kb)

Research paper thumbnail of Differential DNA binding by PLZF and APL associated RAR alpha-PLZF fusion protein

Research paper thumbnail of BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome

International Journal of Molecular Sciences, 2021

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of... more During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regu...

Research paper thumbnail of Human CREBBP acetyltransferase is impaired by etoposide quinone, an oxidative and leukemogenic metabolite of the anticancer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues

Free Radical Biology and Medicine, 2021

Research paper thumbnail of Efficacy of ABT-737, a BCL-2 Inhibitor, in an NRAS/BCL2 Mouse Model of High Risk Myelodysplasia (HR-MDS) By Targeting Pathways Identified By Gene Expression Profiling

Blood, 2014

Background: MDS lack therapeutic approaches in many instances and very few animal models of MDS a... more Background: MDS lack therapeutic approaches in many instances and very few animal models of MDS available for preclinical testing of new drugs have been reported. We have created transgenic animal models of HR-MDS and acute myelogenous leukemia(AML) post-MDS using mutant NRAS and BCL-2 overexpression (Omidvar Cancer Res.2007;67:1657; Rassool Cancer Res. 2007;67:8762) and reported the efficacy of azacitidine in the HR-MDS model (Gorombei Blood 2013;122:1514) and of the BCL2 inhibitor, ABT-737, on the AML post-MDS model (Beurlet Blood 2013;122:2864). The objective of this study was to determine the effects of this inhibitor on our mouse model of HR-MDS. Methods: The mice were followed for disease and once the platelets fell (<1000x103/mm3) at around 3 months, ABT-737 (75mg/kg) was administered every other day for 15 injections. Responses were measured by survival, peripheral blood (PB) counts and Mac1hi/Gr1lo estimations by flow cytometry (FCM) as a measure of circulating blasts. A...

Research paper thumbnail of Identification of PLZF-Dmrs in Hematopoiesis Highlight a Novel Role of PLZF As a Guardian of Hematopoietic Genome Integrity

Blood, 2014

Background: The eucaryotic genome is organized in chromatin domains which affect its function. Th... more Background: The eucaryotic genome is organized in chromatin domains which affect its function. This organization is partly established by special architectural and transcriptional factors specific to the cellular context. In an hematopoietic context, PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the family of POK repressor proteins, is directly implicated in the regulation of epigenetic modifications by tethering DNA methyltransferases (DNMT) and histone deacetylases (HDAC) to specific genomic targets. We have previously shown that PLZF transcriptional activation is controlled by acetylation of specific lysine residues (K647/650/653) affecting its nuclear localization. PLZF is mainly expressed in CD34 positive cells and has been shown to be crucial in the maintenance of hematopoietic stem cells (HSC). However, the epigenetic role of PLZF in HSC protection and maintenance is not yet understood. Methodology: We created PLZF functional knock-in mouse models by introduc...

Research paper thumbnail of Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia–associated TEL-AML1 oncoprotein

Blood, 2000

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombinat... more The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5′-region of the ETS-related gene, TEL(ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 orPEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruit...

Research paper thumbnail of Benzene-Induced Leukemogenesis: Irreversible Inhibition of PTPN2 and Subsequent STAT1 Signaling Alteration By the Hematotoxic Metabolite Benzoquinone

Blood, 2015

Benzene (BZ) is a chemical compound of industrial and toxicological interest classified as a clas... more Benzene (BZ) is a chemical compound of industrial and toxicological interest classified as a class I human carcinogen. Environmental and occupational exposure to BZ lead to bone marrow malignancies such as leukemia. The leukemogenic effects of BZ relies on its metabolization in bone marrow cells into reactive metabolites, in particular benzoquinone (BQ) that can react with macromolecules (arylation) and/or induce oxidative stress. Although BZ is well recognized as a leukemogenic chemical, most of the key molecular and cellular mechanisms underlying its hematotoxicity are not fully understood. PTPN2 is a protein tyrosine phosphatase (PTP) mainly expressed in hematopoietic cells and playing a key role in the homeostasis of the hematopoietic system. In particular, this PTP is an important modulator of growth factors and JAK/STAT signaling pathways. Loss of function analyses in patients with mutation/deletion of the PTPN2 gene and knock-out mouse models indicate that PTPN2 acts as a tum...

Research paper thumbnail of Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling

Journal of Biological Chemistry, 2019

Research paper thumbnail of T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide

Molecular Pharmacology, 2019

Research paper thumbnail of Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia

Research paper thumbnail of GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

Journal of Hematology & Oncology, 2016

Research paper thumbnail of Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

Nature genetics, Jan 12, 2015

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferati... more Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS an...

Research paper thumbnail of Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases

Epigenetics & chromatin, 2015

The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for t... more The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood. In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity ...

Research paper thumbnail of An acetyltransferase assay for CREB-binding protein based on reverse phase–ultra-fast liquid chromatography of fluorescent histone H3 peptides

Analytical Biochemistry, 2015

Research paper thumbnail of Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression

Cancer research, 2005

Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which d... more Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which dramatically responds to all-trans-retinoic acid (ATRA). Recent studies have indicated that combinatorial use of retinoid and nonretinoid compounds, such as histone deacetylase inhibitors, arsenics, and PKA agonists, has higher therapeutic value in this disease and potentially in other malignancies. In a screen of 370 compounds, we identified benzodithiophene analogues as potent enhancers of ATRA-induced APL cell differentiation. These effects were not associated with changes in global histone acetylation and, for the most potent compounds, were exerted at very low nanomolar concentrations, and were paralleled by enhancement of some, but not all, ATRA-modulated gene expressions. Investigating the mechanism underlying the effects of these drugs on ATRA-induced APL cell differentiation, we have shown that benzodithiophenes enhance ATRA-mediated dissociation and association of corepressor N-...

Research paper thumbnail of The PML-RAR alpha gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells

Oncogene, 1994

Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation ... more Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic ac...

Research paper thumbnail of Role of Nuclear Receptor Corepressors in Leukemogenesis

Current Topics in Microbiology and Immunology, 2001

Research paper thumbnail of Acute Promyelocytic Leukemia: A Paradigm for Differentiation Therapy

Acute Myelogenous Leukemia, 2009

Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation lead... more Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARalpha oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.