scholarly journals Not Only Mutations Matter: Molecular Picture of Acute Myeloid Leukemia Emerging from Transcriptome Studies

2019 ◽  
Vol 2019 ◽  
pp. 1-36 ◽  
Author(s):  
Luiza Handschuh
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Circular Rnas ◽  
Gene Expression Measurement ◽  
Protein Coding ◽  
Chimeric Rnas ◽  
Acute Myeloid ◽  
Molecular Picture

The last two decades of genome-scale research revealed a complex molecular picture of acute myeloid leukemia (AML). On the one hand, a number of mutations were discovered and associated with AML diagnosis and prognosis; some of them were introduced into diagnostic tests. On the other hand, transcriptome studies, which preceded AML exome and genome sequencing, remained poorly translated into clinics. Nevertheless, gene expression studies significantly contributed to the elucidation of AML pathogenesis and indicated potential therapeutic directions. The power of transcriptomic approach lies in its comprehensiveness; we can observe how genome manifests its function in a particular type of cells and follow many genes in one test. Moreover, gene expression measurement can be combined with mutation detection, as high-impact mutations are often present in transcripts. This review sums up 20 years of transcriptome research devoted to AML. Gene expression profiling (GEP) revealed signatures distinctive for selected AML subtypes and uncovered the additional within-subtype heterogeneity. The results were particularly valuable in the case of AML with normal karyotype which concerns up to 50% of AML cases. With the use of GEP, new classes of the disease were identified and prognostic predictors were proposed. A plenty of genes were detected as overexpressed in AML when compared to healthy control, includingKIT,BAALC,ERG,MN1,CDX2,WT1,PRAME,andHOXgenes. High expression of these genes constitutes usually an unfavorable prognostic factor. Upregulation ofFLT3andNPM1genes, independent on their mutation status, was also reported in AML and correlated with poor outcome. However, transcriptome is not limited to the protein-coding genes; other types of RNA molecules exist in a cell and regulate genome function. It was shown that microRNA (miRNA) profiles differentiated AML groups and predicted outcome not worse than protein-coding gene profiles. For example, upregulation ofmiR-10a,miR-10b, andmiR-196band downregulation ofmiR-192were found as typical of AML withNPM1mutation whereas overexpression ofmiR-155was associated withFLT3-internal tandem duplication (FLT3-ITD). Development of high-throughput technologies and microarray replacement by next generation sequencing (RNA-seq) enabled uncovering a real variety of leukemic cell transcriptomes, reflected by gene fusions, chimeric RNAs, alternatively spliced transcripts, miRNAs, piRNAs, long noncoding RNAs (lncRNAs), and their special type, circular RNAs. Many of them can be considered as AML biomarkers and potential therapeutic targets. The relations between particular RNA puzzles and other components of leukemic cells and their microenvironment, such as exosomes, are now under investigation. Hopefully, the results of this research will shed the light on these aspects of AML pathogenesis which are still not completely understood.

Collaboration of the Meningioma 1 (MN1) Oncogene with MLL-Fusions in Pediatric Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3786-3786
Author(s):  
Ting Liu ◽  
Dragana Jankovic ◽  
Laurent Brault ◽  
Sabine Ehret ◽  
Vincenzo Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Fusion Genes ◽  
Pediatric Leukemia ◽  
Acute Myeloid

Abstract Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic marker in adult acute myeloid leukemia (AML). In pediatric leukemia, we found overexpression of MN1 in 53 of 88 cases: whereas no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL), significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia. Interestingly, 17 of 19 cases harboring fusion genes involving the mixed-lineage leukemia (MLL-X) gene showed elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM-13). In a mouse model of MLL-ENL-induced leukemia we found MN1 to be overexpressed as a consequence of provirus integration. Strikingly co-expression of MN1 with MLL-ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. Immunophenotyping and secondary transplant experiments suggested that MN1 overexpression seems to expand the L-GMP cell population targeted by the MLL-ENL fusion. Gene expression profiling allowed defining a number of potential MN1 hematopoietic targets. Upregulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse acute myeloid leukemia, as well as in pediatric leukemias with elevated MN1 levels. Our work shows that MN1 is overexpressed in a significant fraction of pediatric acute leukemia, is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-ENL most probably through modification of a distinct gene expression program that leads to expansion of a leukemic progenitor population targeted by MLL-fusion genes.

Gene Expression Patterns Associated with Cytarabine Pharmacology and Outcome in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 114-114
Author(s):  
Jatinder K. Lamba ◽  
Kristine Crews ◽  
Stanley Pounds ◽  
Xueyuan Cao ◽  
Varsha Gandhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Dna Synthesis ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Expression Patterns ◽  
Leukemic Cells ◽  
Leukocyte Counts ◽  
Risk Of Relapse ◽  
Acute Myeloid

Abstract Abstract 114 To identify genes that influence responses to cytarabine (ara-C) treatment, we explored the association of gene expression in leukemic cells at diagnosis with multiple pharmacological and clinical end-points in children with acute myeloid leukemia (AML) treated with ara-C on the St. Jude AML97 clinical trial. We applied a novel statistical procedure, PRojection Onto the Most Interesting Statistical Evidence (PROMISE; PR), to identify genes with expression levels associated with clinical and pharmacological endpoints. To do this, we first defined the following values of the clinical and pharmacological variables as “therapeutically beneficial” :higher leukemic cell ara-C triphosphate levels, lower DNA synthesis values on days 1 and 2 of treatment relative to baseline, decreases in leukocyte counts on day 2 of treatment, improved response and decreased risk of relapse, death, or second malignancy. We considered a gene to show a therapeutically beneficial pattern of association if its expression was positively correlated with ara-CTP levels, negatively correlated with DNA synthesis levels, negatively correlated with decrease in leukocyte counts on day 2, positively correlated with better treatment response, and negativelycorrelated with the risk of relapse or death. A gene showed a therapeutically detrimental pattern of association if its expression had the opposite correlations with the clinical and pharmacological variables. We performed five variable (PR5 using early pharmacologically interesting phenotype measures) or seven variable (PR7 all the above indicated phenotypes) PROMISE analyses. PR5 identified 275 beneficial probe sets and 69 detrimental probe sets (p ≤ 0.005). PR7 analysis identified 112 beneficial probe sets and 115 detrimental probe sets (p ≤ 0.005). To confirm these results, we performed a PROMISE for a cohort of patients treated with ara-C and other agents on the AML02 protocol. Gene expression in leukemic cells at diagnosis was analyzed for a beneficial or detrimental pattern of association with three phenotypes (PR-3); diagnostic blast ara-C cytotoxicity, minimal residual disease (MRD) and event-free survival (EFS). Eighty-one probe sets identified by PR5 or PR7 analyses in the initial cohort were confirmed in the PR-3 analysis of AML02 data. Genes identified in the present study may serve as predictive markers of response and candidates for future drug development. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thyrointegrin αVβ3 Antagonist: Implications in Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4434-4434
Author(s):  
Noureldien Darwish ◽  
Gennadi V. Glinsky ◽  
Shaker A Mousa
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Biological Functions ◽  
Regulated Gene Expression ◽  
Acute Myeloid

Abstract Leukemic cells are able to receive and send several signals within bone marrow niche that play an important role in their survival. One of the important crosstalk is the interaction between the bone marrow microenvironment proteins (vitronectin, fibronectin, fibrinogen, and ostepontin) and thyrointegrin αVβ3 on leukemic cells, generating ligand-specific outside-in signals that are relevant to a variety of cell functions, including gene transcription, cell division, cell attachment, and motility Our previous experiment using in vivo AML animal models with primary AML cells and cell lines have shown significant reduction of leukemic cell burden 74% and >95% (P<0.0001), respectively, after daily subcutaneous treatment with thyrointegrin αvβ3 antagonist fb-PMT (Ki 0.23 nM) at 3 and 10 mg/kg, for 3-4 weeks. In this study we focused on evaluations of the molecular effects of fb-PMT in leukemic cells. Acute myeloid leukemia cell lines (K562-Luc and KG1a cells) were cultured in 50 cm² cell culture flasks with 10 mL phenol red free RPMI media containing 10% fetal bovine albumin. The leukemic cells were treated (at 50% confluence) with 30 µM fb-PMT for 48 hours. Total RNA was immediately isolated from harvested cells using Triazole and used for microarray analysis. Overall, there were 370 significantly down-regulated gene expression records and 273 significantly up-regulated gene expression records, expression of which were changed at least 1.5-fold in fb-PMT-treated human leukemic cells. Significant examples of the fb-PMT-induced gene expression signatures (GES) of pathway's interference include SNAI, MYC, HIF1A, TWIST1, and TFAP2C (P<0.05). Notably, inference of potential contribution to the fb-PMT anticancer activity of the interference with these pathways seems highly congruent with their known biological functions such as cell cycle control (MYC), survival and maintenance of stem cells (HIF1A, TFAP2C), and essential features of the malignant phenotype (TWIST1, SNAI) (Figure 1). Consistently, examples of the fb-PMT-induced GES of transcriptional pathway's activation include RB1, IRF9, MAML1, RAP1A, and GATA4 pathways (P<0.05), known biological functions of which appear highly consistent with the hypothesis that activation of these pathways might contribute to fb-PMT anticancer activity. Finally, we found that fb-PMT interfered with estrogen signaling in human AML cells. The fb-PMT was associated with decreased phosphorylation and nuclear enrichment of Erα (Figure 1). Collectively, our in vivo study and genomic data have shown the key role thyrointegrin αvβ3 in leukemogenesis. The thyrointegrin αvβ3 antagonist fb-PMT demonstrated potent anticancer actions on human AML through the molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long Noncoding RNAs in Acute Myeloid Leukemia: Functional Characterization and Clinical Relevance

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1638 ◽  
Author(s):  
Morgane Gourvest ◽  
Pierre Brousset ◽  
Marina Bousquet
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Functional Characterization ◽  
Noncoding Rnas ◽  
Genetic Alterations ◽  
Long Noncoding Rnas ◽  
Leukemic Cells ◽  
Protein Coding ◽  
Acute Myeloid

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults with an incidence of 4.3 per 100,000 cases per year. Historically, the identification of genetic alterations in AML focused on protein-coding genes to provide biomarkers and to understand the molecular complexity of AML. Despite these findings and because of the heterogeneity of this disease, questions as to the molecular mechanisms underlying AML development and progression remained unsolved. Recently, transcriptome-wide profiling approaches have uncovered a large family of long noncoding RNAs (lncRNAs). Larger than 200 nucleotides and with no apparent protein coding potential, lncRNAs could unveil a new set of players in AML development. Originally considered as dark matter, lncRNAs have critical roles to play in the different steps of gene expression and thus affect cellular homeostasis including proliferation, survival, differentiation, migration or genomic stability. Consequently, lncRNAs are found to be differentially expressed in tumors, notably in AML, and linked to the transformation of healthy cells into leukemic cells. In this review, we aim to summarize the knowledge concerning lncRNAs functions and implications in AML, with a particular emphasis on their prognostic and therapeutic potential.

scholarly journals Knock-in of Dnmt3a R878H Recapitulates Human Acute Myeloid Leukemia Harboring DNMT3A Mutation and Is Highly Responsive to mTOR Inhibitor Rapamycin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2836-2836
Author(s):  
Yujun Dai ◽  
Yueying Wang ◽  
Jinyan Huang ◽  
Li Xia ◽  
Xiaodong Shi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mtor Inhibitor ◽  
Leukemic Cells ◽  
Rna Seq ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Introduction DNMT3A is a gene frequently mutated in human acute myeloid leukemia (AML), with DNMT3A R882H as the hot spot. It had been long postulated that DNMT3A mutation should play a key role in AML pathogenesis, so far the main animal models used were Dnmt3a-/- or transplantation of retrovirally transduced bone marrow cells expressing human DNMT3A R882H mutations (BMT). To recapitulate the features of human AML associated with DNMT3A mutation, this study generated a conditional knock-in mouse model to express Dnmt3a R878H mutation (homologous to human DNMT3A R882H) from the endogenous promoter/enhancer. We investigated epigenetic changes, including gene expression profiles, DNA methylation, and chromatin modification as affected by the mutation. We also explored the potential mechanisms that can explain the process by which DNMT3Amutation hierarchically induces abnormal hematopoiesis and the manner by which specific regulators of relevant pathways in murine and human settings can be targeted for potential therapeutic applications. Method We performed the single-cell RNA-seq (scRNA-seq) of LSKs and MEPs, RNA-seq and Methylated DNA immunoprecipitation sequencing (MeDIP-seq) of Gr-1 cells and whole exome sequence (WES) of BMs and tails in Dnmt3a R878H conditional knock-in mice. Result Approximately 4-6 months after birth with interferon induction, all Dnmt3aR878H/WTMx1-Cre+ knock-in mice developed AML of myelomonocytic subtype, characterized by massive expansion of immature cells and infiltration of bone marrow, spleen and lymph node, along with hyperleukocytosis, thrombocytosis, splenomegaly and lymphadenectasis. The leukemic mice also showed severe diffuse skin ulceration and alopecia. The transcriptome and DNA methylation profiling of bulk Gr-1 leukemic cells and the single-cell RNA-sequencing of LSKs/MEPs revealed significant changes in gene expression and epigenetic regulatory patterns that could cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G2/M phase, CDK1 was found overexpressed as a result of mTOR gene activation due to DNA hypomethylation in the gene body region. We then discovered that overexpressed CDK1 could compete with EZH2 in binding to DNMT3A, induce EZH2 phosphorylation and reduction, and result in abnormal histone methylation. Notably, we showed a very significant response from Dnmt3aR878H/WTto the therapeutic effect of the mTOR inhibitor rapamycin, particularly in terms of prolongation of lifespan in treatment group as compared to the control group (p<0.001). Moreover, rapamycin exerted strong inhibitory effects, including anti-proliferative and apoptosis-induction ones, on human AML cells lines and primary samples from AML patients harboring DNMT3A mutation. Conclusions We established a novel mouse model for the expression of mutant Dnmt3a R878H from endogenous locus to investigate the role of Dnmt3a abnormality in leukemogenesis. Indeed, Dnmt3aR878H/WTMx1-Cre+ mice developed AML of myelomonocytic subtype with skin injury. We discovered unique gene expression and DNA methylation patterns in concordance with enhanced proliferation and suppressed differentiation in leukemic cells. The heterogeneity of gene expression in individual leukemic stem/progenitor cells implied the presence of clonal diversity, which could underlie disease evolution. The activation of mTOR and the resultant overexpression of CDK1 might contribute to malignant transformation. Evidence has been obtained in both murine and human settings to suggest DNMT3A mutation-related AML as a potential disease target for rapamycin. Disclosures No relevant conflicts of interest to declare.

scholarly journals AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia

Blood ◽  
2019 ◽  
Vol 134 (24) ◽  
pp. 2183-2194 ◽  
Author(s):  
Yajian Jiang ◽  
Tianyuan Hu ◽  
Tao Wang ◽  
Xiangguo Shi ◽  
Ayumi Kitano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Myeloid Leukemia ◽  
Metabolic Regulation ◽  
Leukemic Cells ◽  
Epigenetic Changes ◽  
Amp Activated Protein Kinase ◽  
Acute Myeloid

There is increasing evidence that the metabolic regulation of acute myeloid leukemia (AML) cell growth interacts with epigenetic pathways of gene expression and differentiation. Jiang et al link inhibition of glucose metabolism to epigenetic changes and altered transcriptional pathways in leukemic cells and demonstrate synergy between simultaneously targeting metabolism and chromatin modifiers in suppression of AML.

scholarly journals Deregulated expression of circular RNAs in acute myeloid leukemia

2021 ◽  
Vol 5 (5) ◽  
pp. 1490-1503
Author(s):  
Susanne Lux ◽  
Tamara J. Blätte ◽  
Bernhard Gillissen ◽  
Antje Richter ◽  
Sibylle Cocciardi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Gene Expression Signature ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Circular Rnas ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Circular RNAs (circRNAs) are dynamically regulated during differentiation and show cell type–specific expression, which is altered in cancer and can have a direct impact on its various hallmarks. We hypothesized that circRNA expression is deregulated in acute myeloid leukemia (AML) and that circRNA candidates might contribute to the pathogenesis of the disease. To identify leukemia-associated and differentiation-independent changes in circRNA expression, we determined the circular RNAome of 61 AML patients and 16 healthy hematopoietic stem and progenitor cell (HSPC) samples using ribosomal RNA–depleted RNA sequencing. We found hundreds of circRNAs that were differentially expressed between AML and healthy HSPCs. Gene set analysis found that many of these circRNAs were transcribed from genes implicated in leukemia biology. We discovered a circRNA derived from the T-cell transcription factor gene B cell CLL/lymphoma 11B, circBCL11B, which was exclusively expressed in AML patients, but not detected in healthy HSPCs, and associated with a T-cell–like gene expression signature. We were able to validate this finding in an independent cohort of 332 AML patients. Knockdown of circBCL11B had a negative effect on leukemic cell proliferation and resulted in increased cell death of leukemic cells, thereby suggesting circBCL11B as a novel functionally relevant candidate in AML pathogenesis. In summary, our study enables comprehensive insights into circRNA expression changes upon leukemic transformation and provides valuable information on the biology of leukemic cells and potential novel pathway dependencies that are relevant for AML therapy.

scholarly journals Clinical and Biological Features Associated with Engraftment of Acute Myeloid Leukemia Patient-Derived Xenografts

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2858-2858
Author(s):  
Giacomo Oliveira ◽  
Gabriele Bucci ◽  
Cristina Toffalori ◽  
Carolina Caserta ◽  
Lara Crucitti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
In Vivo Growth ◽  
Acute Myeloid

Abstract Background: Patient-derived xenografts (PDXs) are key models for interrogating the biology of tumor cells that poorly survive in vitro. In particular, over the last decade, immunodeficient mouse models have been extensively used to assess the in vivo growth potential of human leukemia, to provide insights into its biology, and to perform preclinical validation of therapies. Still, only a fraction of the cases of acute myeloid leukemia (AML) are able to engraft into mice, and the biological and clinical correlates of the ability to generate PDXs are unknown. Methods: Primary AML harvested from 52 patients at diagnosis (n=37, 71%), at relapse after treatments (n=15, 29%), or both (n=6) were purified and infused into non-irradiated NOD-SCID γ-chain null (NSG) mice. Upon leukemia engraftment, assessed by multiparametric flow cytometry, mice were sacrificed and leukemic cells were isolated, characterized, and reinfused in serial recipients, in up to four serial passages. Gene expression profile was analyzed using Illumina microarray, and deregulated genes and processes identified by pairwise LIMMA analysis and classified using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) curated databases. The mutational asset of infused AML was assessed through targeted resequencing, using a custom panel comprising 192 targets and based on the Agilent Haloplex HS technology. Results: Twenty-six out of 52 primary AML samples (50%) generated xenografts. Engraftment and growth kinetics of the human leukemic cells were highly consistent among littermates, and specific for each tested leukemia. Circulating leukemic cells were firstly detected in the peripheral blood of animals at a median time of 22.5 days (range 14 - 150). In vivo growth allowed expansion of infused AMLs in bone marrows and spleens of the animal, with a median fold increase of 3.5 (range 0.1 - 351.4). The gene expression profile of xenografts was reproducible amongst littermates and recapitulated the features of parental AML: genes deregulated in xenografts accounted for 9.1% of the transcript assessed, with substantial overlap in the genes and processes deregulated in each of the studied cases. GO and GSEA demonstrated the selective deregulation of genes involved in cell proliferation (CDC20, AURKA), syster chromatyde organization (CENPF CEP170) and myeloid differentiation (AZU1, MPO, MYADM, CTSG). Of note, the ability to generate xenografts was conserved when AML cells were challenged at different time-points during the clinical history of the patients, with leukemia harvested at relapse after transplantation displaying a more aggressive behavior. Similarly, upon serial transfer AML exhibited an accelerated growth kinetic. Engraftment in mice significantly correlated with poor patient prognosis: AML engrafters had dramatically lower leukemia free-survival rates compared to non-engrafters (median 5.9 vs. 21.8 months after induction chemotherapy, p=0.0022, Fig. 1A), confirmed also by multivariate analysis (p=0.002). Also the mutational profile differed greatly between engrafters and non-engrafters, as summarized in Fig. 1B. In particular, while the presence of an aberrant karyotype was not associated with PDX generation, FLT3 internal tandem duplication, DNMT3A and NPM1 mutation were all significantly associated to engraftment (p=0.0244, p=0.009 and p=0.0437 respectively). In particular the co-occurrence of mutations in these three genes, recently reported to confer very poor prognosis to AML patients (Papaemmanuil et al, NEJM 2016), markedly enhanced the ability to generate PDXs (Fig.1C). Conclusion: These data show that engraftment into immunodeficient mice mirrors the biology of primary human leukemia, providing a proxy to select cases with a higher chance to generate PDXs. Further comparisons between AML capable or not to generate PDXs might provide novel markers of leukemia aggressiveness and rationales for targeted therapies. Figure 1 Figure 1. Disclosures Bonini: TxCell: Membership on an entity's Board of Directors or advisory committees; Molmed SpA: Consultancy. Ciceri:MolMed SpA: Consultancy.

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