Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Natalie Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G Della Porta.
A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study.
The Lancet Haematology24 Nov 2022, . Epub 24 Nov 2022
Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality.
Myelodysplastic Syndromes with Isolated del(5q): Value of Molecular Alterations for Diagnostic and Prognostic Assessment
Cancers10 Nov 2022, .
Myelodysplastic syndromes (MDS) are a group of clonal hematological neoplasms characterized by ineffective hematopoiesis in one or more bone marrow cell lineages. Consequently, patients present with variable degrees of cytopenia and dysplasia. These characteristics constitute the basis for the World Health Organization (WHO) classification criteria of MDS, among other parameters, for the current prognostic scoring system. Although nearly half of newly diagnosed patients present a cytogenetic alteration, and almost 90% of them harbor at least one somatic mutation, MDS with isolated del(5q) constitutes the only subtype clearly defined by a cytogenetic alteration. The results of several clinical studies and the advances of new technologies have allowed a better understanding of the biological basis of this disease. Therefore, since the first report of the “5q- syndrome” in 1974, changes and refinements have been made in the definition and the characteristics of the patients with MDS and del(5q). Moreover, specific genetic alterations have been found to be associated with the prognosis and response to treatments. The aim of this review is to summarize the current knowledge of the molecular background of MDS with isolated del(5q), focusing on the clinical and prognostic relevance of cytogenetic alterations and somatic mutations.
Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D DiNardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi 9, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami S Komrokji, Mignon L Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Ayalew Tefferi, Elli Papaemmanuil, Andreas Reiter, David Morrall Ross, Michael R Savona, Akiko Shimamura, Radek C Skoda, Francesc Sole, Richard M Stone, Attilio Orazi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola
Genomic Profiling for Clinical Decision Making in Myeloid Neoplasms and Acute Leukemia
Blood21 Sep 2022, .
Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. While assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the last several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole exome sequencing (WES), whole genome sequencing (WGS), and whole transcriptome sequencing (WTS) or RNAseq. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are employed not only for detecting somatically acquired gene mutations, but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias makes extensive use of genomic data. This report aims to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with these hematologic neoplasms.
Adema V, Ma F, Kanagal-Shamanna R, Thongon N, Montalban-Bravo G, Yang H, Peslak SA, Wang F, Acha P, Sole F, Lockyer P, Cassari M, Maciejewski JP, Visconte V, Ganan-Gomez I, Song Y, Bueso-Ramos C, Pellegrini M, Tan TM, Bejar R, Carew JS, Halene S, Santini V, Al-Atrash G, Clise-Dwyer K, Garcia-Manero G, Blobel GA, Colla S
Targeting the EIF2AK1 signaling pathway rescues red blood cell production in SF3B1-mutant myelodysplastic syndromes with ringed sideroblasts.
Blood Cancer Discov4 Aug 2022, . Epub 4 Aug 2022
SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production.
Elsa Bernard, Heinz Tuechler, Peter L. Greenberg, Robert P. Hasserjian, Juan E. Arango Ossa, Yasuhito Nannya, Sean M. Devlin, Maria Creignou, Philippe Pinel, Lily Monnier, Gunes Gundem, Juan S. Medina-Martinez, Dylan Domenico, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Lurdes Zamora, Ronald F. Pinheiro, Andrea Pellagatti, Harold K. Elias, Detlef Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Akifumi Takaori-Kondo, Takayuki Ishikawa, Shigeru Chiba, Senji Kasahara, Yasushi Miyazaki, Agnes Viale, Kety Huberman, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio P. S. Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Kazuma Ohyashiki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Eva Hellström-Lindberg, Elli Papaemmanuil
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes
NEJM Evidence12 Jun 2022, . Epub 12 Jun 2022
Adema V, Palomo L, Walter W, Mallo M, Hutter S, La Framboise T, Arenillas L, Meggendorfer M, Radivoyevitch T, Xicoy B, Pellagatti A, Haferlach C, Boultwood J, Kern W, Visconte V, Sekeres M, Barnard J, Haferlach T, Solé F, Maciejewski JP
Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q
eBioMedicine23 May 2022, 80104059. Epub 23 May 2022
Haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified.
Here, we explored mutations, gene expression and clinical phenotypes of 388 del(5q) vs. 841 diploid cases with MN [82% myelodysplastic syndromes (MDS)].
Del(5q) resulted as founder (better prognosis) or secondary hit (preceded by TP53 mutations). Using Bayesian prediction analyses on 57 HI marker genes we established the minimal del(5q) gene signature that distinguishes del(5q) from diploid cases. Clusters of diploid cases mimicking the del(5q) signature support the overall importance of del(5q) genes in the pathogenesis of MDS in general. Sub-clusters within del(5q) patients pointed towards the inherent intrapatient heterogeneity of HI genes.
The underlying clonal expansion drive results from a balance between the “HI-driver” genes (e.g., CSNK1A1, CTNNA1, TCERG1) and the proapoptotic “HI-anti-drivers” (e.g., RPS14, PURA, SIL1). The residual essential clonal expansion drive allows for selection of accelerator mutations such as TP53 (denominating poor) and CSNK1A1 mutations (with a better prognosis) which overcome pro-apoptotic genes (e.g., p21, BAD, BAX), resulting in a clonal expansion. In summary, we describe the complete picture of del(5q) MN identifying the crucial genes, gene clusters and clonal hierarchy dictating the clinical course of del(5q) patients.
Akkari YMN, Baughn LB, Dubuc AM, Smith AC, Mallo M, Dal Cin P, Díez-Campelo M, Gallego MS, Granada I, Haase DT, Schlegelberger B, Slavutsky I, Mecucci C, Levine RL, Hasserjian RP, Sole F, Levy B, Xu X
Guiding the Global Evolution of Cytogenetic Testing for Hematologic Malignancies.
Blood15 Feb 2022, . Epub 15 Feb 2022
Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies, and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, technical, and economic implications, we provide points to consider for the global evolution of cytogenetic testing.
Rossi M, Meggendorfer M, Zampini M, Tettamanti M, Riva E, Travaglino E, Bersanelli M, Mandelli S, Galbussera AA, Mosca E, Saba E, Chiereghin C, Manes N, Milanesi C, Ubezio M, Morabito L, Peano C, Soldà G, Asselta R, Duga S, Selmi C, De Santis M, Malik K, Maggioni G, Bicchieri ME, Campagna A, Tentori CA, Russo A, Civilini E, Allavena P, Piazza R, Corrao G, Sala C, Termanini A, Giordano L, Detoma P, Malabaila A, Sala L, Rosso S, Zanetti R, Saitta C, Riva E, Condorelli G, Passamonti F, Santoro A, Sole F, Platzbecker U, Fenaux P, Bolli N, Castellani G, Kern W, Vassiliou G, Haferlach T, Lucca U, Della Porta MG
Clinical relevance of clonal hematopoiesis in the oldest-old population.
Blood14 Jun 2021, . Epub 14 Jun 2021
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.