Publications by authors named "Bastien Gerby"

20 Publications

  • Page 1 of 1

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Belgian Cancer Registry, Brussels, Belgium.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as TSLC1, Tumour Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid to myeloid ratio in bone marrow although not altering their multi-lineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM and CBL and mutations of ASXL1, SF3B1 and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2021005311DOI Listing
October 2021

A targetable cue in T-cell malignancy.

Blood 2020 05;135(19):1616-1617

Institute for Research in Immunology and Cancer of Montreal.

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http://dx.doi.org/10.1182/blood.2020005142DOI Listing
May 2020

PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice.

Proc Natl Acad Sci U S A 2018 10 26;115(41):10357-10362. Epub 2018 Sep 26.

Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III Paul Sabatier (UPS), 31037 Toulouse, France;

is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed to the coding sequence of elastin (). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on , , , and genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
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http://dx.doi.org/10.1073/pnas.1721678115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187160PMC
October 2018

and isoforms are both efficient to drive B cell differentiation.

Oncotarget 2018 Aug 28;9(67):32841-32854. Epub 2018 Aug 28.

Inserm, UMR1037 CRCT, F-31000, Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Oncopole, F-31000 Toulouse, France.

Pax5 is the guardian of the B cell identity since it primes or enhances the expression of B cell specific genes and concomitantly represses the expression of B cell inappropriate genes. The tight regulation of is therefore required for an efficient B cell differentiation. A defect in its dosage can translate into immunodeficiency or malignant disorders such as leukemia or lymphoma. is expressed from two different promoters encoding two isoforms that only differ in the sequence of their first alternative exon. Very little is known regarding the role of the two isoforms during B cell differentiation and the regulation of their expression. Our work aims to characterize the mechanisms of regulation of the expression balance of these two isoforms and their implication in the B cell differentiation process using murine analyses. We show that these two isoforms are differentially regulated but have equivalent function during early B cell differentiation and may have functional differences after B cell activation. The tight control of their expression may thus reflect a way to finely tune Pax5 dosage during B cell differentiation process.
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http://dx.doi.org/10.18632/oncotarget.26003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132355PMC
August 2018

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.

J Clin Invest 2016 12 31;126(12):4569-4584. Epub 2016 Oct 31.

Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non-cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy.
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http://dx.doi.org/10.1172/JCI86489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127686PMC
December 2016

SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells.

PLoS Genet 2014 Dec 18;10(12):e1004768. Epub 2014 Dec 18.

Institute of Research in Immunology and Cancer - University of Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL.
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http://dx.doi.org/10.1371/journal.pgen.1004768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270438PMC
December 2014

Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression.

EMBO Mol Med 2014 Jun 6;6(6):821-34. Epub 2014 Apr 6.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA) DSV-IRCM-SCSR-LSHL Equipe Labellisée Ligue Contre le Cancer UMR 967, Fontenay-aux-Roses, France INSERM U967, Fontenay-aux-Roses, France Université Paris Diderot Sorbonne Paris Cité UMR 967, Fontenay-aux-Roses, France Université Paris-Sud UMR 967, Fontenay-aux-Roses, France

Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.
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http://dx.doi.org/10.1002/emmm.201303286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203358PMC
June 2014

Genetic interaction between Kit and Scl.

Blood 2013 Aug 8;122(7):1150-61. Epub 2013 Jul 8.

Institute for Research in Immunology and Cancer, Montréal, QC, Canada.

SCL/TAL1, a tissue-specific transcription factor of the basic helix-loop-helix family, and c-Kit, a tyrosine kinase receptor, control hematopoietic stem cell survival and quiescence. Here we report that SCL levels are limiting for the clonal expansion of Kit⁺ multipotent and erythroid progenitors. In addition, increased SCL expression specifically enhances the sensitivity of these progenitors to steel factor (KIT ligand) without affecting interleukin-3 response, whereas a DNA-binding mutant antagonizes KIT function and induces apoptosis in progenitors. Furthermore, a twofold increase in SCL levels in mice bearing a hypomorphic Kit allele (W41/41) corrects their hematocrits and deficiencies in erythroid progenitor numbers. At the molecular level, we found that SCL and c-Kit signaling control a common gene expression signature, of which 19 genes are associated with apoptosis. Half of those were decreased in purified megakaryocyte/erythroid progenitors (MEPs) from W41/41 mice and rescued by the SCL transgene. We conclude that Scl operates downstream of Kit to support the survival of MEPs. Finally, higher SCL expression upregulates Kit in normal bone marrow cells and increases chimerism after bone marrow transplantation, indicating that Scl is also upstream of Kit. We conclude that Scl and Kit establish a positive feedback loop in multipotent and MEPs.
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http://dx.doi.org/10.1182/blood-2011-01-331819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952531PMC
August 2013

Modelling acute leukemias in mice: clonal evolution and the emergence of leukemic stem cells.

BMC Proc 2013 4;7 Suppl 2:K1. Epub 2013 Apr 4.

Institute of Research in Immunology and Cancer, University of Montréal, Montréal, Québec, Canada H3C 3J7 ; Molecular Biology Program, University of Montréal, Montréal, Québec, Canada H3C 3J7 ; Departments of Medicine, University of Montréal, Montréal, Québec, Canada H3C 3J7 ; Department of Pharmacology. University of Montréal, Montréal, Québec, Canada H3C 3J7 ; Department of Biochemistry, University of Montréal, Montréal, Québec, Canada H3C 3J7.

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http://dx.doi.org/10.1186/1753-6561-7-S2-K1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624666PMC
April 2015

Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.

J Exp Med 2012 Oct 8;209(11):2017-31. Epub 2012 Oct 8.

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 985, 94805 Villejuif, France.

Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.
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http://dx.doi.org/10.1084/jem.20121343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478932PMC
October 2012

Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.

Cell 2012 Aug;150(3):575-89

Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
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http://dx.doi.org/10.1016/j.cell.2012.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613864PMC
August 2012

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.

J Exp Med 2011 Apr 4;208(4):653-61. Epub 2011 Apr 4.

Laboratoire de Recherche sur les Cellules Souches Hématopoïétiques et Leucémiques, Institut de Radiobiologie Cellulaire et Moléculaire, Commissariat à l'Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux-Roses, France.

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.
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http://dx.doi.org/10.1084/jem.20110105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135355PMC
April 2011

NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia.

J Exp Med 2010 Sep 20;207(10):2141-56. Epub 2010 Sep 20.

Laboratoire de recherche sur la Réparation et la Transcription dans les cellules Souches, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux-Roses, France.

TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1-expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1-LMO-Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.
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http://dx.doi.org/10.1084/jem.20100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947082PMC
September 2010

Iodination increases the activity of verapamil derivatives in reversing PGP multidrug resistance.

Anticancer Res 2010 Jul;30(7):2553-9

University of Grenoble I, Department of Molecular Chemistry, UMR CNRS 5250, F-38041, Grenoble Cedex 9, France.

Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.
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July 2010

[Demonstration of leukemic stem cells in the human T-ALLs and study of the involvement of the NOTCH, TAL1 and ERK/MAPK pathways in human T-leukemogenesis].

Ann Pathol 2008 Nov 17;28 Spec No 1(1):S28-9. Epub 2008 Oct 17.

Laboratoire des cellules souches hématopoïétiques et leucémiques, institut de radiobiologie moléculaire et cellulaire, CEA, 18, route de Panorama, BP 6, 92265 Fontenay-aux-Roses, France.

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http://dx.doi.org/10.1016/j.annpat.2008.09.004DOI Listing
November 2008

NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity.

Blood 2009 Feb 4;113(8):1730-40. Epub 2008 Nov 4.

Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104 Paris, France.

Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.
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http://dx.doi.org/10.1182/blood-2008-02-138172DOI Listing
February 2009

2-Arylidenedihydroindole-3-ones: design, synthesis, and biological activity on bladder carcinoma cell lines.

Bioorg Med Chem Lett 2007 Jan 16;17(1):208-13. Epub 2006 Oct 16.

Laboratoire de Dynamique Cellulaire, EPHE, UMR-CNRS 5525, IFRT 130, Université Joseph Fourier, Pavillon Taillefer, 38706 La Tronche Cedex, France.

2-Arylidenedihydroindole-3-ones were assayed for their antiproliferative and apoptotic abilities as potential drug candidates to treat bladder tumor. These compounds were tested on cell lines obtained from bladder tumors of various stages [superficial (pTa and pT1) vs. invasive (pT2)]. The most active compound (3c) inhibited the proliferation, induced apoptosis, and decreased the expression of p-Stat5 and p-Pyk2 in DAG-1 and RT112 lines in which the FGFR3 is either mutated or overexpressed. Knowing that FGFR3 is involved in cell proliferation, differentiation, and migration through cell signaling pathways including p-Stat5 way via p-Pyk2, let us assume that compound 3c may probably act through FGFR3 pathway.
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http://dx.doi.org/10.1016/j.bmcl.2006.09.057DOI Listing
January 2007

Piperazinobenzopyranones and phenalkylaminobenzopyranones: potent inhibitors of breast cancer resistance protein (ABCG2).

J Med Chem 2005 Nov;48(23):7275-81

Département de Pharmacochimie Moléculaire, UMR-CNRS 5063, Faculté de Pharmacie de Grenoble, 5, Avenue de Verdun, BP 138, 38243 Meylan, France.

In continuing research that led us to identify chromanone derivatives (J. Med. Chem. 2003, 46, 2125) as P-glycoprotein inhibitors, we obtained analogues able to modulate multidrug resistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of 5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitors of BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, we evaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and the cytotoxic effect of the anticancer drug, mitoxantrone. At 10 microM, three compounds increased both intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with a comparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potent molecules 5b and 5c are still active at 1 microM, whereas FTC shows weak inhibition. These molecules do not induce cell death as shown by the cell cycle distribution study, which makes them potential candidates for in vivo studies.
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http://dx.doi.org/10.1021/jm050705hDOI Listing
November 2005
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