Publications by authors named "Francois Delhommeau"

58 Publications

Unexplained recurrent implantation failures: Predictive factors of pregnancy and therapeutic management from a French multicentre study.

J Reprod Immunol 2021 Mar 22;145:103313. Epub 2021 Mar 22.

Sorbonne Université, APHP, Service de Médecine Interne, Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DMU i3), F-75012, Paris, France. Electronic address:

Introduction: Recurrent implantation failure is defined as the absence of pregnancy after at least three transfers of good-quality embryos after in vitro fecundation/intracytoplasic sperm injection.

Aim: The aim of this study was to describe a multicentre cohort of women with unexplained RIF, to analyse the factors associated with clinical pregnancy and to evaluate the immunomodulatory therapies efficacy.

Methods: Women were consecutively recruited from university departments with unexplained RIF.

Results: Sixty-four women were enrolled with mean age 36 ± 3 years. The rates of clinical pregnancy in 64 women were compared in untreated and treated cycles and according to therapies used during the last prospectively followed embryo transfer. A clinical pregnancy after the transfer was noted in 56 % pregnancies on intralipids and in 50 % on prednisone, versus 5 % in untreated ones (p < 0.001). The 340 embryo transfers of these 64 women resulted in 68 clinical pregnancies and 18 live births. Clinical pregnancies were significantly more frequent in treated versus untreated embryo transfers (44 % vs 9 %; p < 0.001) with odds ratio at 8.13 (95 % CI 4.49-14.72, p < 0.0001). Cumulative pregnancy rates were higher for steroid-treated transfers than for untreated transfers when considering overall transfers before and after using steroids and also only those under steroids. Cumulative pregnancy rates were not different from steroid- and intralipid-treated embryo transfers CONCLUSIONS: In this multicentre study of women with unexplained RIF, use of immunomodulatory treatments before embryo transfer resulted in higher clinical pregnancy. Randomised, well-designed studies in well-defined population of RIF women are necessary to confirm our preliminary data.
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http://dx.doi.org/10.1016/j.jri.2021.103313DOI Listing
March 2021

Unexplained recurrent miscarriages: predictive value of immune biomarkers and immunomodulatory therapies for live birth.

Am J Reprod Immunol 2021 Mar 27:e13425. Epub 2021 Mar 27.

Sorbonne Université Service de Gynécologie Obstétrique, Hôpital Armand-Trousseau, Paris, France.

Introduction: Recurrent miscarriages are defined as three or more early miscarriages before 12 weeks of gestation. The aim of this study was to describe a cohort of women with unexplained recurrent miscarriages, evaluate several potential biomarkers of immune origin, and describe the outcome of pregnancies under immunomodulatory therapies.

Methods: Women having a history of at least 3 early miscarriages without any etiology were recruited from 3 university hospitals.

Results: Among 101 women with recurrent miscarriages, overall, 652 pregnancies have been included in the analysis. Women which experienced miscarriages were older (33.3 ± 5.4 versus 31.9 ± 6.7; p = 0.03), with history of more pregnancies (4 (2-6) versus 3.5 (1-5.75); p 0.0008), and less frequently the same partner (406 (74%) versus 79 (86%); p=0.01). There was no difference in the level and frequencies of biomarkers of immune origin (NK, lymphocyte, gamma globulins and blood cytokine levels and endometrial uNK activation status), except the higher rates of positive antinuclear antibodies in women with live birth (12 (13%) versus 36 (7%); p=0.03). Among the 652 pregnancies, 215 (33%) have been treated and received either aspirin/low weighted molecular heparin (LMWH) and/or combined to different lines of immunomodulatory treatment. Patients with pregnancy under treatment had a significantly higher rate of cumulative live birth rate than those with untreated ones (43.0% vs 34.8%; p = 0.04). When compared to patients with untreated pregnancies, patients with steroids during the pregnancy had twice more chances to obtain live birth (OR 2.0, CI95% 1.1 - 3.7, p = 0.02).

Conclusions: Unexplained recurrent miscarriages could have improved obstetrical outcome under immunomodulatory therapies and in particular steroids.
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http://dx.doi.org/10.1111/aji.13425DOI Listing
March 2021

VEXAS syndrome: still expanding the clinical phenotype.

Rheumatology (Oxford) 2021 Mar 8. Epub 2021 Mar 8.

AP-HP, Hôpital Saint Antoine, service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Sorbonne Université, Paris, F-75012, France.

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http://dx.doi.org/10.1093/rheumatology/keab225DOI Listing
March 2021

High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers.

Blood Adv 2020 08;4(15):3550-3557

Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.
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http://dx.doi.org/10.1182/bloodadvances.2020001582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422125PMC
August 2020

Clonal haematopoiesis is increased in early onset in systemic sclerosis.

Rheumatology (Oxford) 2020 11;59(11):3499-3504

Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine (CRSA).

Objectives: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype.

Methods: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors.

Results: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP.

Conclusion: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored.
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http://dx.doi.org/10.1093/rheumatology/keaa282DOI Listing
November 2020

Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy.

Leukemia 2021 03 24;35(3):712-723. Epub 2020 Jun 24.

Service Hématologie Adultes, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-0932-8DOI Listing
March 2021

Annexin-A5 resistance and non-criteria antibodies for the diagnosis of seronegative antiphospholipid syndrome.

Clin Rheumatol 2020 Apr 10;39(4):1167-1171. Epub 2020 Jan 10.

Sorbonne Université, Service de Médecine Interne, APHP SAint Antoine, 75012, Paris, France.

In this study, we aimed to analyze the value of annexin-A5 anticoagulant ratio (A5R) and non-criteria antibodies for the diagnosis of APS in patients with clinical seronegative APS. Three groups were defined, including 21 seronegative APS patients with unexplained obstetrical adverse events or thrombosis history, 15 confirmed APS patients with triple aPL positivity, and a control group of 20 healthy patients without any history of thrombosis or pregnancy complications. Seronegative APS patients have similar levels of A5R in comparison to healthy controls (202% [171%-238%] versus 191% [178%-221%]; p = 0.65), whereas triple-positive APS patients have significantly more reduced A5R in comparison to both seronegative and healthy patients (149% [138%-158%] versus 202% [171%-238%] and 191% [178%-221%], respectively, p < 0.001). The non-criteria aPL were found in 24% of seronegative APS: anti-PE IgM in 3 cases (14%) and anti-PS/PT IgG and anti-PS/PT IgM in 1 (5%) case each. The frequency of non-criteria APL was significantly more frequent in comparison to healthy controls (p = 0.048). All triple-positive APS patients have at least one non-criteria aPL, and the non-criteria aPL were significantly more frequent in these patients compared to seronegative APS and healthy controls (p < 0.001). Whereas A5R levels do not allow to discriminate seronegative APS from healthy controls, our results demonstrate that non-criteria aPL can help to APS diagnosis in clinical seronegative APS.Key points• Annexin-A5 resistance testing does not help for the diagnosis of seronegative APS.• The non-criteria antiphospholipid antibodies can contribute to APS diagnosis in patients without conventional antibodies.
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http://dx.doi.org/10.1007/s10067-019-04915-5DOI Listing
April 2020

Fractionated gemtuzumab ozogamicin in association with high dose chemotherapy: a bridge to allogeneic stem cell transplantation in refractory and relapsed acute myeloid leukemia.

Bone Marrow Transplant 2020 02 25;55(2):452-460. Epub 2019 Sep 25.

Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.

Optimization of the salvage regimen is required to improve prognosis in primary refractory or relapsed acute myeloid leukemia (AML). In fit patients, a bridge to allogeneic transplant is the primary purpose of salvage. We tested the combination of fractionated gemtuzumab ozogamicin with cytarabine and mitoxantrone (MYLODAM schema) with primary endpoint of efficacy and safety. We also attempted to define predictive factors for survival and response after salvage. We included 58 patients with a median age at salvage of 56 years. The overall response rate was 67%. Leukemia-free survival (LFS) and overall survival (OS) at 2 years was 36% (95% CI: 23-49) and 54% (95% CI: 39-68), respectively. Treatment-related mortality was 7%. Three veno-occlusive diseases (SOS/VOD) occurred during salvage. In the allogeneic group of 28 patients (48%), LFS and OS at 2 years was 57 % (95% CI: 36.3-77.5) and 69 % (95% CI: 49.3-88.7), respectively. Incidences of nonrelapse mortality, grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 16%, 40%, and 45%, respectively. A GO-based intensive regimen is a viable option for salvage therapy and a feasible schedule as a bridge to allogeneic transplant.
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http://dx.doi.org/10.1038/s41409-019-0690-2DOI Listing
February 2020

Targeted molecular characterization shows differences between primary and secondary myelofibrosis.

Genes Chromosomes Cancer 2019 Jul 24. Epub 2019 Jul 24.

Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, Marseille, France.

Introduction: In BCR-ABL1-negative myeloproliferative neoplasms, myelofibrosis (MF) is either primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocythemia. MF is characterized by an increased risk of transformation to acute myeloid leukemia (AML) and a shortened life expectancy.

Methods: Because natural histories of PMF and SMF are different, we studied by targeted next generation sequencing the differences in the molecular landscape of 86 PMF and 59 SMF and compared their prognosis impact.

Results: PMF had more ASXL1 (47.7%) and SRSF2 (14%) gene mutations than SMF (respectively 27.1% and 3.4%, P = .04). Poorer survival was associated with RNA splicing mutations (especially SRSF2) and TP53 in PMF (P = .0003), and with ASXL1 and TP53 mutations in SMF (P < .0001). These mutations of poor prognosis were associated with biological features of scoring systems (DIPSS and MYSEC-PM score). Mutations in TP53/SRSF2 in PMF or TP53/ASXL1 in SMF were more frequent as the risk of these scores increased. This allowed for a better stratification of MF patients, especially within the DIPSS intermediate-1 risk group (DIPSS) or the MYSEC-PM high risk group. AML transformation occurred faster in SMF than in PMF and patients who transformed to AML were more SRSF2-mutated and less CALR-mutated at MF sampling.

Conclusions: PMF and SMF have different but not specific molecular profiles and different prognosis depending on the molecular profile. This may be due to differences in disease history. Combining mutations and existing scores should improve prognosis assessment.
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http://dx.doi.org/10.1002/gcc.22789DOI Listing
July 2019

Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis.

Arch Immunol Ther Exp (Warsz) 2019 Aug 30;67(4):225-236. Epub 2019 May 30.

Sorbonne Universités, UPMC Université Paris 06, UMR 7211, Service de Médecine Interne, Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DHU i2B), 75005, Paris, France.

We aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3CD56) and T-cell large granular lymphocytes (CD8CD57) during preconception in a homogenous group of women with unexplained well-defined recurrent miscarriage (RM) and repeated implantation failure (RIF) vs healthy controls in relation to pregnancy outcomes. This case-control study followed by a literature review and meta-analysis was conducted in three university hospitals. Patients and controls were consecutively recruited from December 2015 to October 2017. In total, 115 women were included in the study: 54 with RM, 41 with RIF and 20 healthy controls with ≥ 2 term births. Percentages of CD3CD56 and CD8CD57 cells and sub-populations of CD3CD56 cells did not differ between cases and controls. The results for women with subsequent miscarriage did not differ from those with live births. The meta-analysis of the literature showed higher NK-cell proportions in RM [mean difference 3.47 (95% CI 2.94-4.00); p < 0.001] and RIF [mean difference 1.64 (95% CI 0.82-2.45); p < 0.001] than controls. However, the heterogeneity between the different studies was high. The proportion of peripheral blood CD3CD56 and CD8CD57 cells in the preconception period does not reflect the risk of implantation failure or miscarriage and should not be recommended indicators for the management of RM and RIF. Further prospective large studies are needed to develop a reliable peripheral blood marker of immune deregulation.
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http://dx.doi.org/10.1007/s00005-019-00546-5DOI Listing
August 2019

Chronic myelomonocytic leukaemia associated with large- and medium-sized arteries vasculitis of the small bowel.

Rheumatology (Oxford) 2019 10;58(10):1882-1883

Department of Internal Medicine and Inflammatory Disorders (DHU i2B), Hôpital Saint-Antoine AP-HP Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1093/rheumatology/kez187DOI Listing
October 2019

Systemic Dysfunction of Osteoblast Differentiation in Adipose-Derived Stem Cells from Patients with Multiple Myeloma.

Cells 2019 05 10;8(5). Epub 2019 May 10.

Sorbonne Université, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Département d'Hématologie et de Thérapie Cellulaire, F-75012 Paris, France.

multiple myeloma; bone disease; osteogenesis; adipogenesis; adipose-derived stem cells; bone marrow; senescence; Dickkopf-related protein 1; systemic disease.
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http://dx.doi.org/10.3390/cells8050441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562713PMC
May 2019

Genetic Hierarchy of Acute Myeloid Leukemia: From Clonal Hematopoiesis to Molecular Residual Disease.

Int J Mol Sci 2018 Dec 3;19(12). Epub 2018 Dec 3.

Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Hématologie Biologique, F-75012 Paris, France.

Recent advances in the field of cancer genome analysis revolutionized the picture we have of acute myeloid leukemia (AML). Pan-genomic studies, using either single nucleotide polymorphism arrays or whole genome/exome next generation sequencing, uncovered alterations in dozens of new genes or pathways, intimately connected with the development of leukemia. From a simple two-hit model in the late nineties, we are now building clonal stories that involve multiple unexpected cellular functions, leading to full-blown AML. In this review, we will address several seminal concepts that result from these new findings. We will describe the genetic landscape of AML, the association and order of events that define multiple sub-entities, both in terms of pathogenesis and in terms of clinical practice. Finally, we will discuss the use of this knowledge in the settings of new strategies for the evaluation of measurable residual diseases (MRD), using clone-specific multiple molecular targets.
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http://dx.doi.org/10.3390/ijms19123850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321602PMC
December 2018

Chronic myelogenous leukemia occurring in a chronic lymphocytic leukemia patient.

Clin Case Rep 2018 Aug 4;6(8):1655-1656. Epub 2018 Jul 4.

Inserm, Centre de Recherche Saint-Antoine CRSA, APHP, Hôpital Saint-Antoine Sorbonne Université Paris France.

Occurrence of two different hematological malignancies is very infrequent, and it is nevertheless important not to neglect basic examinations in patients follow-up. A 65-year-old patient was referred to our institution for his chronic lymphocytic leukemia (CLL) checkup; we report the different steps leading to the diagnosis of a second hematological malignancy.
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http://dx.doi.org/10.1002/ccr3.1572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099060PMC
August 2018

Myelodysplastic syndrome (MDS) with isolated trisomy 8: a type of MDS frequently associated with myeloproliferative features? A report by the Groupe Francophone des Myélodysplasies.

Br J Haematol 2018 09 13;182(6):843-850. Epub 2018 Jul 13.

Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), University Paris Diderot (Paris 7), Paris, France.

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 × 10 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39·1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33·3% vs. 12·0% in non-MP, P = 0·047), ASXL1 (66·7% vs. 42·3%, P = 0·048) and STAG2 mutations (77·8% vs. 21·7%, P = 0·006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0·15) and 39 months (P = 0·085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms.
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http://dx.doi.org/10.1111/bjh.15490DOI Listing
September 2018

Control in dormancy or eradication of cancer stem cells: Mathematical modeling and stability issues.

J Theor Biol 2018 07 17;449:103-123. Epub 2018 Apr 17.

Sorbonne Université, GRC n7, Groupe de Recherche Clinique sur les Myéloproliferations Aiguës et Chroniques, AP-HP, Hôpital Saint-Antoine, Paris F-75012, France. Electronic address:

Objective: Modeling and analysis of cell population dynamics enhance our understanding of cancer. Here we introduce and explore a new model that may apply to many tissues.

Analyses: An age-structured model describing coexistence between mutated and ordinary stem cells is developed and explored. The model is transformed into a nonlinear time-delay system governing the dynamics of healthy cells, coupled to a nonlinear differential-difference system describing dynamics of unhealthy cells. Its main features are highlighted and an advanced stability analysis of several steady states is performed, through specific Lyapunov-like functionals for descriptor-type systems.

Results: We propose a biologically based model endowed with rich dynamics. It incorporates a new parameter representing immunoediting processes, including the case where proliferation of cancer cells is locally kept under check by the immune cells. It also considers the overproliferation of cancer stem cells, modeled as a subpopulation of mutated cells that is constantly active in cell division. The analysis that we perform here reveals the conditions of existence of several steady states, including the case of cancer dormancy, in the coupled model of interest. Our study suggests that cancer dormancy may result from a plastic sensitivity of mutated cells to their shared environment, different from that - fixed - of healthy cells, and this is related to an action (or lack of action) of the immune system. Next, the stability analysis that we perform is essentially oriented towards the determination of sufficient conditions, depending on all the model parameters, that ensure either a regionally (i.e., locally) stable dormancy steady state or eradication of unhealthy cells. Finally, we discuss some biological interpretations, with regards to our findings, in light of current and emerging therapeutics. These final insights are particularly formulated in the paradigmatic case of hematopoiesis and acute leukemia, which is one of the best known malignancies for which it is always hard, in presence of a clinical and histological remission, to decide between cure and dormancy of a tumoral clone.
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http://dx.doi.org/10.1016/j.jtbi.2018.03.038DOI Listing
July 2018

mutations: the dawn of Shwachman clones.

Blood 2018 01;131(4):376-377

Sorbonne Université.

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http://dx.doi.org/10.1182/blood-2017-11-815431DOI Listing
January 2018

Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors.

Biol Blood Marrow Transplant 2018 05 11;24(5):1013-1021. Epub 2018 Jan 11.

Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; UMRS 938, Inserm, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France. Electronic address:

The results of conventional allogeneic stem cell transplantation (SCT) in refractory hematologic malignancies are poor. Sequential strategies have shown promising results in refractory acute myelogenous leukemia (AML), but have not been validated in a haploidentical (Haplo) transplant setting. We have developed a new sequential approach combining chemotherapy with broad antitumor activity (thiotepa 10 mg/kg, etoposide 400 mg/m, and cyclophosphamide 1600 mg/m from day -15 to day -10), followed after 3 days of rest by a reduced-intensity conditioning regimen (fludarabine 150 mg/m, i.v. busulfan 6.4 mg/kg, and thymoglobulin 5 mg/kg from day -6 to day -2). High-dose post-transplantation cyclophosphamide was added in cases with Haplo donors. Seventy-two patients (median age, 54 years) with a refractory hematologic malignancy (44 with acute myelogenous leukemia, 7 with acute lymphoblastic leukemia, 15 with myelodysplastic syndrome/myeloproliferative neoplasms, and 6 with lymphomas) were included in this retrospective multicenter study. Donors were Haplo (n = 27), matched related (MRD; n = 16), and unrelated (UD; n = 29). With a median follow-up of 21 months, the 2-year overall survival (OS) and event-free survival (EFS) were 54.7% and 49.3%, respectively, in recipients of Haplo transplants, 49.2% and 43.8%, respectively, in recipients of MRD transplants, and 37.9% and 28%, respectively, in recipients of UD transplants. Compared with UD, the outcomes were improved in Haplo in terms of the incidences of acute grade II-IV graft-versus-host disease (GVHD) (11.1% versus 41.4%; P < .001) and GVHD-free, relapse-free survival (44.4 versus 10.3%; P = .022). These results support the safety and efficacy of a thiotepa-based sequential approach in allogeneic SCT with a Haplo donor with post-transplantation immune modulation. Thus, in patients with refractory hematologic malignancies, there seems to be no benefit in searching for a UD when a Haplo donor is readily available.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.005DOI Listing
May 2018

Expression of CD94 by -differentiated NK cells correlates with the and acquisition of cytotoxic features.

Oncoimmunology 2017;6(10):e1346763. Epub 2017 Jul 18.

U1186-INSERM, Equipe labellisée Ligue contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, France.

The administration of -expanded Natural Killer (NK) cells in leukemia therapy is still challenging, in part due to the difficulty to generate in sufficient quantities fully mature and functional NK cells and Identification of surface markers indicative of NK maturation and functionality is therefore needed. Here, based on the analysis of surface receptors of -expanded NK cells, we identified CD94 as a surface marker correlating with high lytic potential against leukemic cell lines and immunological synapse formation. CD94-positive -expanded NK cells displayed higher expression of NKG2 receptors and the adhesion molecule LFA-1, as compared with their CD94-negative counterparts. We also tested the anti-leukemic capacity of -expanded NK cells against patient-derived acute myeloid leukemia cells. Although no anti-leukemic effect was detected, we noticed that only CD94-positive -expanded NK cells were detected in leukemic mice at the end of the 2-week treatment. Moreover, flow cytometry analysis showed a subpopulation harboring CD94 (NK) and CD34 (leukemic cells) double staining, indicative of conjugate formation. Therefore surface expression of CD94 on -differentiated NK cells emerged as an indicator of and killer cell functionality.
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http://dx.doi.org/10.1080/2162402X.2017.1346763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665075PMC
July 2017

Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143).

Sci Rep 2017 08 4;7(1):7305. Epub 2017 Aug 4.

INSERM, UMR 1170, 114 rue Edouard Vaillant, 94805, Villejuif, France.

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17 and P15 models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.
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http://dx.doi.org/10.1038/s41598-017-07848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544749PMC
August 2017

Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.

Cancer Discov 2017 07 17;7(7):716-735. Epub 2017 Apr 17.

Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.

Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis , we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease. AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36-FAO-OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501738PMC
July 2017

Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia.

Haematologica 2017 07 16;102(7):1227-1237. Epub 2017 Mar 16.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, APHP Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine (CRSA), Paris

The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases.
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http://dx.doi.org/10.3324/haematol.2016.159681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566032PMC
July 2017

Reed Sternberg cell/lymphocyte rosettes in a bone marrow aspirate leading to the diagnosis of Hodgkin lymphoma.

Br J Haematol 2016 11 24;175(4):557. Epub 2016 Aug 24.

AP-HP, Hôpital Saint-Antoine & Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012, Paris, France.

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http://dx.doi.org/10.1111/bjh.14301DOI Listing
November 2016

Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

Nat Commun 2016 08 18;7:12475. Epub 2016 Aug 18.

Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.
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http://dx.doi.org/10.1038/ncomms12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992157PMC
August 2016

Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.

J Exp Med 2016 Apr 7;213(4):483-97. Epub 2016 Mar 7.

Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Research Center of Toulouse, U1037, F-31024 Toulouse, France Université de Toulouse, F-31300 Toulouse, France

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rγ(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.
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http://dx.doi.org/10.1084/jem.20150736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821643PMC
April 2016

Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution.

Leuk Res 2014 Aug 4;38(8):907-12. Epub 2014 Jun 4.

Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; UPMC, Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.

The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML.
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http://dx.doi.org/10.1016/j.leukres.2014.05.021DOI Listing
August 2014

TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells.

Stem Cells 2014 Aug;32(8):2084-97

Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France; Institut Gustave Roussy, Villejuif, Paris, France; Université Paris Sud 11, Orsay, France.

Ten-eleven-translocation 2 (TET2) belongs to the TET protein family that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine and plays a central role in normal and malignant adult hematopoiesis. Yet the role of TET2 in human hematopoietic development remains largely unknown. Here, we show that TET2 expression is low in human embryonic stem cell (ESC) lines and increases during hematopoietic differentiation. shRNA-mediated TET2 knockdown had no effect on the pluripotency of various ESCs. However, it skewed their differentiation into neuroectoderm at the expense of endoderm and mesoderm both in vitro and in vivo. These effects were rescued by reintroducing the targeted TET2 protein. Moreover, TET2-driven differentiation was dependent on NANOG transcriptional factor. Indeed, TET2 bound to NANOG promoter and in TET2-deficient cells the methylation of the NANOG promoter correlated with a decreased in NANOG expression. The altered differentiation resulting from TET2 knockdown in ESCs led to a decrease in both the number and the cloning capacities of hematopoietic progenitors. These defects were due to an increased apoptosis and an altered gene expression profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm and hematopoietic differentiation.
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http://dx.doi.org/10.1002/stem.1718DOI Listing
August 2014

CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia.

Oncotarget 2013 Sep;4(9):1438-48

Inserm, U1016, Institut Cochin, F-75014, Paris, France.

The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824541PMC
http://dx.doi.org/10.18632/oncotarget.1195DOI Listing
September 2013

Applying ecological and evolutionary theory to cancer: a long and winding road.

Evol Appl 2013 Jan 16;6(1):1-10. Epub 2012 Nov 16.

MIVEGEC (UMR CNRS/IRD/UM1) 5290 Montpellier Cedex 5, France ; CREEC Montpellier Cedex 5, France.

Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.
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http://dx.doi.org/10.1111/eva.12021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567465PMC
January 2013