Publications associées à Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: open questions

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

PURPOSE The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammali ...

2023

Novel quantitative bioengineered tools to track human bone marrow niche cellular constituents in health and disease

Rita Sarkis

Acute leukemia has a high mortality rate of approximately 50%, and current methods are not effective in predicting disease progression and relapse. To improve our understanding of hematopoiesis and develop new markers for predicting disease relapse in dead ...

EPFL2023

Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1(T315I) and BCR-ABL1(T315I-E255K)

Oliver Hantschel

Resistance remains the major clinical challenge for the therapy of Philadelphia chromosome-positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common "gatekeeper" mutation T315I ...

SPRINGER2021

Notch Signaling - a Booster of Chronic Lymphocytic Leukemia During Initiation and Disease Progression

Delphine Maude Tardivon

Chronic lymphocytic leukemia (CLL) is a B cell malignancy and represents the most common leukemia in adults within the Western world. This disease mainly affects the elderly, with a median age of diagnosis over 70. The disease course is highly variable amo ...

EPFL2020

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

Hilal Lashuel, Anass Chiki, Nadine Aït Bouziad, Galina Limorenko

The microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau's norma ...

2020

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

Jörg Hülsken, Anja Irmisch, Oliver Hantschel

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ ...

2019

Allosteric kinase inhibitors

Oliver Hantschel

Background. Inhibition of the kinase activity of the BCR-ABL1 oncoprotein by an allosteric mechanism of action facilitates alternative treatment options for chronic myeloid leukemia (CML) patients who cannot be adequately treated with conventional catalyti ...

Springer Nature2017

Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics

Romain Hamelin, Oliver Hantschel, Sandrine Madeleine Suzanne Georgeon, Sina Maren Reckel

The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p190, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p190 occurs in the majority of B-cell acute lymphobl ...

Nature Publishing Group2017

Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase

Florence Pojer, Oliver Hantschel, Sandrine Madeleine Suzanne Georgeon, Delphine Maude Tardivon, Sina Maren Reckel, Barbara Gerig, Tim Kükenshöner, Sara Raquel Pereira Pinho, Charlotte Julie Caroline Gehin

The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study ...

Springer Nature2017

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34(+) Stem/Progenitor Cells

Michel Aguet, Maximilien Murone, Andres McAllister, Stefania Rigotti

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (T ...

Amer Assoc Cancer Research2017

Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function

Oliver Hantschel, Tim Kükenshöner

Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g. T618I), functionally defective mutations in the extracellular domain of the granulocyte colony-stimulating factor receptor (CSF3R) have been reported only in seve ...

American Association for Cancer Research2017

CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy

Jeffrey David Jensen, Sebastian Matuszewski

Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehe ...

National Academy of Sciences2017

Allosteric regulation and targeting of Abl SH2-kinase interface and other cytoplasmic tyrosine kinases

Allan Joaquim Lamontanara

Due to their central role in normal cellular physiology, the activity of protein kinases is tightly regulated and their aberrant activation can lead to cancer. Chronic myelogenous leukemia (CML) is a blood cancer characterized by unregulated growth of myel ...

EPFL2016

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Oliver Hantschel

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examine ...

American Society of Hematology2016

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface

Oliver Hantschel, Allan Joaquim Lamontanara, Barbara Gerig

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase do ...

American Society for Biochemistry and Molecular Biology2016

Targeting BCR-ABL and JAK2 in Ph+ ALL

Oliver Hantschel

In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus ...

2015

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity

Oliver Hantschel

Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies ha ...

Portland Press2015

Functional Perturbation of the Gab2 Multiprotein Complex by High-affinity SH2-binding Monobodies in Chronic Myelogenous Leukemia

Emel Basak Gencer Akçok

Chronic myeloid leukemia is characterized by a reciprocal chromosomal translocation between chromosome 9 and 22, resulting in the expression of the Bcr-Abl oncoprotein. Despite the great improvement in patient survival using tyrosine kinase inhibitors (TKI ...

EPFL2015

Improved Angiostatic Activity of Dasatinib by Modulation with Hydrophobic Chains

Paul Joseph Dyson, Patrycja Nowak-Sliwinska, Catherine Marie Amélie Clavel, Emilia Paunescu

Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-beta and SFKs in both tumor cells and tumor associated endothelial cells, dasatinib inhibits tumor growth and angiogenes ...

Amer Chemical Soc2015

6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

Jeffrey Alan Hubbell, Melody Swartz, Iraklis Kourtis, Laura Jeanbart

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles eff ...

Springer2015