Ali G Turhan

University of Paris-Saclay

The TOPASE study was set up to evaluate the outcomes of chronic myeloid leukaemia [CML] patients treated with ponatinib (PON) in a real‐world setting in France. One hundred and twenty CML patients, 105 in chronic phase (CP), 8 in accelerated phase (AP) and 7 in blastic phase (BP) were included. Fifty‐one (49%) of the CP‐CML patients were in third l...

Purpose The ability to generate natural killer (NK) cells from induced pluripotent stem cells (iPSCs) has given rise to new possibilities for the large-scale production of homogeneous immunotherapeutic cellular products and opened new avenues towards the creation of “off-the-shelf” cancer immunotherapies. However, the differentiation of NK cells fr...

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been descri...

Rearranged during Transfection (RET) oncogenic rearrangements can occur in 1-2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has been described yet. Patient-derived iPSCs hold great promise for disease modeling. However,...

Despite the development of new immunotherapy strategies, lung cancer remains the leading cause of cancer-related deaths. One of the reasons is attributed to the persistence of cancer stem cells (CSCs) within the tumor, contributing to drug resistance, dormancy and metastatic spread. To eradicate CSCs, iPSC-based vaccination represents a novel appro...

The iPSC-derived NK (iNK) cells offer new perspectives to produce large-scale of homogeneous immunotherapeutic cellular products and open the way towards manufacturing off-the-shelf cancer immunotherapies. Numerous strategies and protocols of differentiation of iPSCs toward NK lineage have been published in the last decade. Nevertheless, the embryo...

Somatic cells that have been partially reprogrammed by the factors Oct4, Sox2, Klf4, and cMyc (OSKM) have been demonstrated to be potentially tumorigenic in vitro and in vivo due to the acquisition of cancer-associated genomic alterations and the absence of OSKM clearance over time. In the present study we obtained partially reprogrammed, SSEA1-neg...

The embryonic development of the pig comprises a long in utero pre- and peri-implantation development, which dramatically differs from mice and humans. During this peri-implantation period, a complex series of paracrine signals establishes an intimate dialogue between the embryo and the uterus. To better understand the biology of the pig blastocyst...

During the last two decades, the introduction of tyrosine kinase inhibitors (TKIs) to the therapy has changed the natural history of CML but progression into accelerated and blast phase (AP/BP) occurs in 3-5% of cases, especially in patients resistant to several lines of TKIs. In TKI-refractory patients in advanced phases, the only curative option...

REarranged during Transfection (RET) oncogenic rearrangements can occur in 1–2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has yet been described. Patient-derived iPSCs hold great promise for disease modeling and drug s...

Background The use of tyrosine kinase inhibitors (TKIs) has dramatically modified the therapy of chronic myeloid leukemia (CML), generating durable remissions and prolonging survival in TKI-responders. However, progression to blast crisis (BC) still occurs especially in TKI-resistant patients and represents a clinical challenge. We and others have...

Tyrosine kinase inhibitor (TKI) therapies have profoundly changed the natural history and survival of CML patients. However, the majority of the patients remain on long-lasting therapies and switch one TKI to another, either because of intolerance or resistance. All TKI cessation trials showed approximately 50% of leukemia recurrence rates even aft...

Background Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma characterized by the translocation t(11;14)(q13;q32) which triggers the dysregulation of the cyclin D1 by placing its coding gene CC1ND1 under the control of an immunoglobulin promoter. One of the major consequences of this molecular event is the disturbance of the cyclin...

Acute myeloid leukemia (AML) with BCR::ABL1 has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity by integrating clonal architecture a...

Generating Hematopoietic Stem Cells (HSCs) from Pluripotent Stem Cells (PSCs) has been a long-lasting quest in the field of hematopoiesis. Previous studies suggested that enforced expression of BCR-ABL, the unique oncogenic driver of Chronic Myelogeneous Leukemia (CML), in Embryonic Stem Cells (ESCs)-derived hematopoietic cells is sufficient to con...

The early embryonic development of the pig comprises a long in utero pre- and peri-implantation development, which dramatically differs from mouse and human. During this pro-tracted peri-implantation period, an intimate dialogue between the embryo and the uterus is established through a complex series of paracrine signals. It leads to concomitant d...

Introduction: Previous studies have suggested that the tyrosine kinase receptor RET plays a sig-nificant role in the hematopoietic potential in mice and could also be used to expand cord-blood derived hematopoietic stem cells (HSCs). The role of RET in the human iPSC-derived hematopoi-esis has not been tested so far. Methods: To test the implicatio...

Methods: We used a patient-specific induced pluripotent stem cell (iPSC) line treated with the mutagenic agent N-ethyl-N-nitrosourea (ENU). Genomic instability was validated using γ-H2AX and micronuclei assays and CGH array for genomic events. Results: An increased number of progenitors (x5-Fold), which proliferated in liquid cultures with a bla...

Objective: Chronic myeloid leukemia (CML) is a disease caused by the acquisition of BCR-ABL1 fusion in a hematopoietic stem cell. In this study, we focused on the oncofoetal ENOX2 protein as a potential secretable biomarker in CML. Material and methods: We used cell culture, Western blot, quantitative RT-PCR, ELISA, transcriptome analyses and bi...

The classical natural history of chronic myeloid leukemia (CML) has been drastically modified by the introduction of tyrosine kinase inhibitor (TKI) therapies. TKI discontinuation is currently possible in patients in deep molecular responses, using strict recommendations of molecular follow-up due to risk of molecular relapse, especially during the...

Purpose: To model CML progression in vitro and generate a blast crisis (BC-CML) model in vitro in order to identify new targets. Methods: Three different CML-derived iPSC lines were mutagenized with the alkylating agent ENU on a daily basis for 60 days. Cells were analyzed at D12 of hematopoietic differentiation for their phenotype, clonogenicit...

Generating Hematopoietic Stem Cells (HSCs) from Pluripotent Stem Cells (PSCs) has been a long-lasting quest in the field of hematopoiesis. Previous studies suggested that enforced expression of BCR-ABL, the unique oncogenic driver of Chronic Myelogeneous Leukemia (CML), in Embryonic Stem Cells (ESCs)-derived hematopoietic cells is sufficient to con...

Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy driven by the BCR-ABL1 fusion oncoprotein. The development of tyrosine kinase inhibitors (TKIs) has deeply increased long-term survival of CML patients. Nonetheless, one patient out of four will switch TKI off owing either to drug intolerance or resistance partly due to amplificati...

Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy driven by the BCR::ABL1 fusion oncoprotein. The development of tyrosine kinase inhibitors (TKIs) has deeply increased long-term survival of CML patients. Nonetheless, one patient out of four will switch TKI off owing either to drug intolerance or resistance partly due to amplificat...

Using induced Pluripotent Stem Cell (iPSC) technology, it is now possible to reprogram the primary leukemic cells to pluripotency and generate a major source of stem cells. To determine the feasibility of modeling global genomic instability characterizing chronic myeloid leukemia (CML) progression towards blast crisis (BC), we have used a patient-s...

Guidelines for tyrosine kinase inhibitor (TKI)-treated chronic phase-chronic myeloid leukemia (CML) management are essentially based on data from clinical research trials; however, real-world data should be valuable for optimizing such recommendations. Here, we analyzed the data collected in the French CML Observatory database, a multicenter real-w...

Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1–STN1–TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated...

Hemangioblasts derived from mesodermal lineage are the earliest precursors of hematopoietic stem cells and endothelial cells. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) are the only experimental systems in which these cells can be assayed and quantified. We show here using CML-derived iPSC and blast-cell colony forming (Bl...

Cancer is maintained by the activity of a rare population of self-renewing “cancer stem cells” (CSCs), which are resistant to conventional therapies. CSCs over-express several proteins shared with induced pluripotent stem cells (iPSCs). We show here that allogenic or autologous murine iPSCs, combined with a histone deacetylase inhibitor (HDACi), ar...

Progress made during the last decade in stem cell biology allows currently an unprecedented potential to translate these advances into the clinical applications and to shape the future of regenerative medicine. Organoid technology is amongst these major developments, derived from primary tissues or more recently, from induced pluripotent stem cells...

Background During aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The precise molecular mechanisms of this phenomenon are not well established. To uncover the molecular events underlying this event, we have performed a bioinformatics analysis of 650 single-cell transcriptomes. Methods...

Background The worldwide pandemic caused by the SARS-CoV-2 virus is characterized by significant and unpredictable heterogeneity in symptoms that remains poorly understood. Methods Transcriptome and single cell transcriptome of COVID19 lung were integrated with deeplearning analysis of MHC class I immunopeptidome against SARS-COV2 proteome. Resul...

Background In mammalians, hematopoietic stem cells (HSCs) arise in the dorsal aorta from the hemogenic endothelium, followed by their migration to the fetal liver and to the bone marrow. In zebrafish, the kidney is the site of primary hematopoiesis. In humans, the presence of HSCs in the fetal or adult kidney has not been established. Methods We a...

Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a...

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the acquisition of BCR-ABL1 fusion in a hematopoietic stem cell. We identified the ENOX2 gene as up-regulated in BCR-ABL1-expressing UT-7 cell lines through a transcriptome assay. The oncofoetal ENOX2 protein (Ecto-Nicotinamide Adenine Dinucleotide Oxidase Disulfide Thiol Exc...

Background In mammalians, hematopoietic stem cells (HSC) arise in the dorsal aorta from the hemogenic endothelium, followed by their migration to fetal liver and to bone marrow. In zebrafish, kidney is the site of primary hematopoiesis. In humans, the presence of HSC in the fetal or adult kidney has not been established. Methods We analyzed the pr...

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targ...

The use of mesenchymal stem cells (MSC) derived from several sources as a major anti-inflammation strategy has been suggested in the recent outbreak of Coronavirus-19 (COVID-19). As the virus enters the target cells through the receptor ACE2, it is important to determine if the MSC population transfused to patients could also be a target for the vi...

The molecular mechanisms of cytokine storm in patients with severe COVID-19 infections are poorly understood. To uncover these events, we performed transcriptome analyses of lung biopsies from patients with COVID-19, revealing a gene enrichment pattern similar to that of PPARγ-knockout macrophages. Single-cell gene expression analysis of bronchoalv...

Background Vast transcriptomics and epigenomics changes are characteristic of human cancers including leukemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exempla...

Research on chronic and acute myeloid leukemia (CML/AML) is focused on the development of novel therapeutic strategies to eliminate leukemic stem/progenitor cells that are responsible for drug resistance and disease relapse. Methods to culture hematopoietic stem/progenitor cells (HSPCs) from blood or bone marrow samples are indispensable for invest...

Investigation of human hematopoietic stem cells (HSCs) has been revolutionized by advances in cell separation and clonal tracking of cells produced in transplanted patients and immunodeficient mice. However, methods able to expand them significantly remain elusive. iPSCs are of continuing interest as an alternative source, although robust condition...

Hemangioblasts derived from mesodermal lineage are the earliest precursors of hematopoietic stem cells and endothelial cells. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) are the only experimental systems in which these cells can be assayed and quantified. We show here using CML-derived iPSC and blast-cell colony forming (Bl...

Chronic myeloid leukemia (CML) is characterized by an inherent genetic instability, which contributes to the progression of the disease towards an accelerated phase (AP) and blast crisis (BC). Several cytogenetic and genomic alterations have been reported in the progression towards BC, but the precise molecular mechanisms of this event are undeterm...

We successfully converted hepatocytes isolated from adult mice into expandable and stable leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive endodermal progenitor cells (EndoPCs). This was accomplished in vitro through transient exposure to four transcriptional factors (OCT3/4, SOX2, KLF4, and cMYC) and STAT3 activators. En...

Cancer is maintained by the activity of a rare population of self-renewing cancer stem cells (CSCs), which are resistant to conventional therapies. CSCs share several antigenic determinants with pluripotent stem cells (PSCs). We show here that PSCs, combined with a histone deacetylase inhibitor (HDACi), are able to elicit major anti-tumor responses...

Recent experimental data suggest that the heterogeneity of CML stem cells can be due to the development of unique molecular events generating functional consequences in terms of the resistance and persistence of leukemic stem cells (LSC). In order to explore this phenomenon, we have designed a single cell transcriptome assay evaluating simultaneous...

Background: Current experimental models using either human or mouse cell lines, are not representative of the complex features of GBM. In particular, there is no model to study patient-derived iPSCs to generate a GBM model. Overexpression of c-met gene is one of the molecular features of GBM leading to increased signaling via STAT3 phosphorylation...

Chronic myeloid leukemia (CML) is characterized by an inherent genetic instability, which contributes to the progression of the disease towards accelerated and blast crisis (BC). The occurrence of the latter has been hampered by the use of tyrosine kinase inhibitors (TKI), which changed this natural progression, but BC still occurs in patients resi...

Defective in Chromatid Joining (DIS3) is a highly conserved exoribonuclease, involved in the 3'-5' degradation of RNAs, which has a major role as a post-transcriptional checkpoint in eukaryotic cells. The controlled degradation of unnecessary RNA transcripts from the cell by the DIS3 family enzymes has been shown to be essential for cell division a...

Acute myeloid leukemias (AMLs) are heterogenous diseases often resulting from the acquisition of multiple genetic alterations that deregulate hematopoietic precursor proliferation and block normal differentiation. Chronic myeloid leukemia offers a unique opportunity to identify molecular mechanisms that interfere with normal differentiation in the...

Ponatinib is a third generation tyrosine kinase inhibitor (TKI) indicated in the treatment of CML-chronic phase (CP), accelerated phase (AP) and blast phase (BP) as well as in patients with the gatekeeper T315I mutation. TOPASE is the real life observatory initiated in France with the participation of 40 CML centers. We report here the interim resu...

Chronic myeloid leukemia (CML) represents one of the major success stories of targeted therapies of the 21st century with the use of tyrosine kinase inhibitors (TKIs). Following discontinuation of TKIs in deep molecular remission context, at least half of the patients experience molecular relapse. Cellular events occurring during this phase are not...

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carc...

Patient-specific, tumor-derived organoids represent a powerful novel technology to model cancer, but the requirement of collection of fresh tumor cells and low efficiency of organoid generation represents significant bottlenecks. The induced pluripotent stem cell (iPSC) technology offers the possibility to generate an unlimited and reproducible sou...

Patient-specific, tumor-derived organoids represent a powerful novel technology to model cancer, but the requirement of collection of fresh tumor cells and low efficiency of organoid generation represents significant bottlenecks. The induced pluripotent stem cell (iPSC) technology offers the possibility to generate an unlimited and reproducible sou...

Recent development of cell reprogramming technologies brought a major hope for future cell therapy applications by the use of these cells or their derivatives. For this purpose, one of the major requirements is the absence of genomic alterations generating a risk of cell transformation. Here we analyzed by microarray-based comparative genomic hybri...

Although human pluripotent stem cells (hPSCs) can theoretically differentiate into any cell type, their ability to produce hematopoietic cells is highly variable from one cell line to another. The underlying mechanisms of this heterogeneity are not clearly understood. Here, using a whole miRNome analysis approach in hPSCs, we discovered that their...

Over the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate induced pluripotent stem cells (iPSCs)...

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis as a driving oncogenic event is present in germline, exposing the healthy member of a family to the occurrence of cancer. The study of the secondary events in a tissue-specific manner is now possible by the induced pluripotent stem cell (iPSC) technol...

The use of tyrosine kinase inhibitors (TKI) has dramatically changed the natural history and the prognosis of CML with a major improvement of survival in patients responding to therapy. However, tyrosine kinase inhibitor (TKI) discontinuation trials in patients with deep molecular responses (DMR), show that 50-60% of patients will have a molecular...

Although human pluripotent stem cells (hPSCs) can theoretically be differentiated into any cell type, their ability to generate hematopoietic cells shows a major variability from one cell line to another. The reasons of this variable differentiation potential, which is constant and reproducible in a given hPSC line, are not clearly established. In...