Publications by authors named "Gianni Cazzaniga"

28 Publications

  • Page 1 of 1

More than an 'atypical' phenotype: dual molecular diagnosis of autoimmune lymphoproliferative syndrome and Becker muscular dystrophy.

Br J Haematol 2020 10 19;191(2):291-294. Epub 2020 Jul 19.

Pediatric Hematology Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy.

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http://dx.doi.org/10.1111/bjh.16967DOI Listing
October 2020

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

Blood 2021 Jan;137(4):493-499

Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy.

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.
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http://dx.doi.org/10.1182/blood.2020006441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845007PMC
January 2021

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.

Blood Adv 2019 11;3(21):3393-3405

Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA.

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
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http://dx.doi.org/10.1182/bloodadvances.2019000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855112PMC
November 2019

Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.

Haematologica 2020 07 10;105(7):1887-1894. Epub 2019 Oct 10.

Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy.

ABL-class fusions other than characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: .
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http://dx.doi.org/10.3324/haematol.2019.231720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327633PMC
July 2020

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

Cancer Cell 2019 04;35(4):649-663.e10

Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland. Electronic address:

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1 B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1 B-ALL.
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http://dx.doi.org/10.1016/j.ccell.2019.03.005DOI Listing
April 2019

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia.

Transl Oncol 2019 May 13;12(5):726-732. Epub 2019 Mar 13.

Molecular Cancer Study Group, Division of Clinical Research, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. Electronic address:

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
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http://dx.doi.org/10.1016/j.tranon.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423364PMC
May 2019

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.

Haematologica 2019 06 24;104(6):1176-1188. Epub 2019 Jan 24.

Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1 (MLL-AF4) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, "multi-layered" genome-wide analyses and validation were performed on a total of 124 cases of infant B-cell acute lymphoblastic leukemia uniformly diagnosed and treated according to the Interfant 99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in and , were subclonal and were frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11) infant B-cell acute lymphoblastic leukemia, and RNA-sequencing showed transcriptomic similarities between t(4;11) infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem and progenitor cells, confirming a "pre-VDJ" fetal cellular origin for both t(4;11) and The reciprocal fusion was expressed in only 45% (19/43) of the t(4;11) patients, and HOXA cluster genes are exclusively expressed in -expressing patients. Importantly, /-expressing patients had a significantly better 4-year event-free survival (62.4% 11.7%, =0.001), and overall survival (73.7 25.2%, =0.016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to the Interfant-06 protocol based on age at diagnosis, white blood cell count and response to prednisone. This study has clinical implications for disease outcome and diagnostic risk-stratification of t(4;11) infant B-cell acute lymphoblastic leukemia.
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http://dx.doi.org/10.3324/haematol.2018.206375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545849PMC
June 2019

: a new player in myeloid cell differentiation.

Haematologica 2019 07 10;104(7):1332-1341. Epub 2019 Jan 10.

Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, LITA, Segrate, Italy

The nucleophosmin 1 gene () is the most frequently mutated gene in acute myeloid leukemia. Notably, mutations are always accompanied by additional mutations such as those in cohesin genes , , , and but not in the cohesin regulator, nipped B-like (). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and mutation and observed a specific reduction in the expression of but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of also induced downregulation of , the zebrafish ortholog of human To investigate the hematopoietic phenotype and the interaction between mutated and , we generated a zebrafish model with downregulation which showed an increased number of myeloid progenitors. This phenotype was due to hyper-activation of the canonical Wnt pathway: myeloid cells blocked in an undifferentiated state could be rescued when the Wnt pathway was inhibited by mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for during zebrafish hematopoiesis and suggest that an interplay between may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation.
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http://dx.doi.org/10.3324/haematol.2018.200899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601076PMC
July 2019

Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.

Br J Haematol 2019 03 26;184(6):974-981. Epub 2018 Dec 26.

Genetica Umana e Medica, Dipartimento di Medicina e Chirurgia, Università dell'Insubria, Varese, Italy.

In Shwachman-Diamond syndrome (SDS), deletion of the long arm of chromosome 20, del(20)(q), often acquired in bone marrow (BM), may imply a lower risk of developing myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), due to the loss of the EIF6 gene. The genes L3MBTL1 and SGK2, also on chromosome 20, are in a cluster of imprinted genes, and their loss implies dysregulation of BM function. We report here the results of array comparative genomic hybridization (a-CGH) performed on BM DNA of six patients which confirmed the consistent loss of EIF6 gene. Interestingly, array single nucleotide polymorphisms (SNPs) showed copy neutral loss of heterozygosity for EIF6 region in cases without del(20)(q). No preferential parental origin of the deleted chromosome 20 was detected by microsatellite analysis in six SDS patients. Our patients showed a very mild haematological condition, and none evolved into BM aplasia or MDS/AML. We extend the benign prognostic significance of del(20)(q) and loss of EIF6 to the haematological features of these patients, consistently characterized by mild hypoplastic BM, no or mild neutropenia, anaemia and thrombocytopenia. Some odd results obtained in microsatellite and SNP-array analysis demonstrate a peculiar genomic instability, in an attempt to improve BM function through the acquisition of the del(20)(q).
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http://dx.doi.org/10.1111/bjh.15729DOI Listing
March 2019

Modeling Cornelia de Lange syndrome in vitro and in vivo reveals a role for cohesin complex in neuronal survival and differentiation.

Hum Mol Genet 2019 01;28(1):64-73

Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.

Cornelia de Lange syndrome (CdLS), which is reported to affect ∼1 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five genes: nipped-B-like protein, structural maintenance of chromosomes 1A, structural maintenance of chromosomes 3, RAD21 cohesin complex component and histone deacetylase 8 (HDAC8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development. Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells (NSCs) and in vertebrate (Danio rerio) brain development by knockdown and chemical inhibition experiments. Underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs or in zebrafish embryos.
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http://dx.doi.org/10.1093/hmg/ddy329DOI Listing
January 2019

A Novel Inducible Mouse Model of -driven Mixed-lineage Acute Leukemia.

Hemasphere 2018 Aug 12;2(4):e51. Epub 2018 Jun 12.

Department of Biomedicine, University Children's Hospital of Basel, Basel, Switzerland.

Previous retroviral and knock-in approaches to model human t(11;19) acute mixed-lineage leukemia in mice resulted in myeloproliferation and acute myeloid leukemia not fully recapitulating the human disease. The authors established a doxycycline (DOX)-inducible transgenic mouse model "" in which induction in long-term hematopoietic stem cells, lymphoid primed multipotent progenitor cells, multipotent progenitors (MPP4) but not in more committed myeloid granulocyte-macrophage progenitors led to a fully reversible acute leukemia expressing myeloid and B-cell markers. leukemic cells generally expressed lower mRNA than those obtained after retroviral transduction. Disease induction was associated with levels exceeding the endogenous at mRNA and protein levels. In leukemic cells from t(11;19) leukemia patients, mRNA also exceeded the endogenous levels suggesting a critical threshold for transformation. Expression profiling of acute leukemia revealed gene signatures that segregated t(11;19) leukemia patients from those without an MLL translocation. Importantly, B220 leukemic cells showed a higher in vivo leukemia initiation potential than coexisting B220 cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell-of-origin and the fusion gene expression levels are both critical determinants for -driven acute leukemia.
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http://dx.doi.org/10.1097/HS9.0000000000000051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745998PMC
August 2018

Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4 Infant ALL.

Mol Cancer Ther 2018 08 10;17(8):1705-1716. Epub 2018 May 10.

Centro Ricerca Tettamanti, Pediatric Clinic, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.

-rearranged acute lymphoblastic leukemia (ALL) occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with -rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein, we have investigated the effects of bromodomain and extra-terminal (BET) function abrogation in a preclinical mouse model of MLL-AF4 infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4 leukemic cells , by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 impairs the leukemic engraftment of patient-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of -rearranged ALL through the deregulation of , and gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoid-resistant -rearranged cells to prednisolone and is more efficient when used in combination with HDAC inhibitors, both and Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat -rearranged infant ALL for future clinical applications. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1123DOI Listing
August 2018

An update on PCR use for minimal residual disease monitoring in acute lymphoblastic leukemia.

Expert Rev Mol Diagn 2017 11 21;17(11):953-963. Epub 2017 Sep 21.

a Tettamanti Research Center, Department of Pediatrics , University of Milano Bicocca , Monza , Italy.

Introduction: Acute lymphoblastic leukemia (ALL) is the first neoplasm where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has proven to be a fundamental tool for guiding therapeutic choices. In recent years, thanks to real-time quantitative PCR (qPCR), MRD monitoring has further achieved higher levels of sensitivity and standardization. However, some outstanding issues still remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients. Areas covered: Through a comprehensive review of the literature, we analyze the state-of-the-art of molecular MRD assessment in ALL to better understand how, in the upcoming years, some of its limitations could be tackled by emerging molecular technologies. Furthermore, we highlight the future role of molecular MRD monitoring in the context of personalized protocols, taking into account the growing genetic complexity in ALL. Expert commentary: Although new molecular technologies are promising tools for MRD assessment, qPCR still remains the gold standard for evaluating MRD in ALL. High-throughput sequencing and droplet digital PCR allow to identify new prognostic factors and/or MRD targets at diagnosis and to perform earlier MRD evaluations, thereby optimizing patient stratification and earlier MRD-based clinical intervention to improve ALL patient outcomes.
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http://dx.doi.org/10.1080/14737159.2017.1377073DOI Listing
November 2017

High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges.

J Immunol 2017 05 17;198(10):3765-3774. Epub 2017 Apr 17.

Institute of Applied Biosciences, Center for Research and Technology Hellas, GR-57001 Thessaloniki, Greece.

Analysis and interpretation of Ig and TCR gene rearrangements in the conventional, low-throughput way have their limitations in terms of resolution, coverage, and biases. With the advent of high-throughput, next-generation sequencing (NGS) technologies, a deeper analysis of Ig and/or TCR (IG/TR) gene rearrangements is now within reach, which impacts on all main applications of IG/TR immunogenetic analysis. To bridge the generation gap from low- to high-throughput analysis, the EuroClonality-NGS Consortium has been formed, with the main objectives to develop, standardize, and validate the entire workflow of IG/TR NGS assays for 1) clonality assessment, 2) minimal residual disease detection, and 3) repertoire analysis. This concerns the preanalytical (sample preparation, target choice), analytical (amplification, NGS), and postanalytical (immunoinformatics) phases. Here we critically discuss pitfalls and challenges of IG/TR NGS methodology and its applications in hemato-oncology and immunology.
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http://dx.doi.org/10.4049/jimmunol.1602050DOI Listing
May 2017

High expression of miR-125b-2 and SNORD116 noncoding RNA clusters characterize ERG-related B cell precursor acute lymphoblastic leukemia.

Oncotarget 2017 Jun;8(26):42398-42413

Department of Women's and Children's Health, University of Padova, Padova, Italy.

ERG-related leukemia is a B cell precursor acute lymphoblastic leukemia (BCP ALL) subtype characterized by aberrant expression of DUX4 and ERG transcription factors, and highly recurrent ERG intragenic deletions. ERG-related patients have remarkably favorable outcome despite a high incidence of inauspicious IKZF1 aberrations.We describe clinical and genomic features of the ERG-related cases in an unselected cohort of B-other BCP ALL pediatric patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a small noncoding RNA signature specific of ERG-related group, with up-regulation of miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster.
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http://dx.doi.org/10.18632/oncotarget.16392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522075PMC
June 2017

Acute myeloid leukemia in Baraitser-Winter cerebrofrontofacial syndrome.

Am J Med Genet A 2017 Feb 21;173(2):546-549. Epub 2016 Nov 21.

Clinical Genetic Pediatric Unit, Pediatric Department of MBBM Foundation, S. Gerardo Hospital, Monza, Italy.

Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Baraitser-Winter cerebrofrontofacial syndrome (BWCFF), which is characterized by facial dysmorphism, ocular coloboma, brain malformations, and intellectual disabilities. In addition to that, the recent discovery of missense mutations in one of the two ubiquitously expressed cytoplasmic β- and γ-acting-encoding genes ACTB (7p22.1) and ACTG1 (17q25.3) in patients carrying a clinical diagnosis of BWSM, FA, or CCF has provided further evidence that these clinical conditions do indeed belong to the same entity at the molecular level. Two cases of BWCFF patients presenting with malignancies (i.e., acute lymphocytic leukemia and cutaneous lymphoma) have been published thus far. Here, we report a 21-year-old female with molecularly confirmed FA, who developed acute myeloid leukemia (AML). The present finding may indicate that actinopathies could be cancer-predisposing syndromes although small numbers and publication bias should be taken into account. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38057DOI Listing
February 2017

Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

Stem Cell Reports 2016 10 22;7(4):602-618. Epub 2016 Sep 22.

Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; Instituciò Catalana de Recerca i Estudis Avançats (ICREA), 08036 Barcelona, Spain. Electronic address:

Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.
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http://dx.doi.org/10.1016/j.stemcr.2016.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063541PMC
October 2016

CyclinD1 Down-Regulation and Increased Apoptosis Are Common Features of Cohesinopathies.

J Cell Physiol 2016 Mar;231(3):613-22

Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates.
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http://dx.doi.org/10.1002/jcp.25106DOI Listing
March 2016

Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations.

Blood 2014 Dec 30;124(24):3577-82. Epub 2014 Sep 30.

Hematology Unit, University of Perugia, Polo Unico S.M. Misericordia, Perugia, Italy;

MYC translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ∼6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYC translocations were significantly associated with the TAL/LMO subtype of T-ALL (P = .018) and trisomies 6 (P < .001) and 7 (P < .001). Within the TAL/LMO subtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYC translocations; specifically, 77 were upregulated and 71 downregulated in those with MYC translocations. The poor prognostic marker, CD44, was among the upregulated genes. MYC translocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse.
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http://dx.doi.org/10.1182/blood-2014-06-578856DOI Listing
December 2014

Low PKCα expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome.

Oncotarget 2014 Jul;5(14):5234-45

Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.

Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels above the threshold, presented a markedly increased cumulative incidence of relapse (43.8% vs. 10.9%, P<0.001), as well as a worse 4-year overall survival (66% vs. 87.9%, P=0.002) and event-free survival (53.1% vs. 85.2%, P=0.002). In particular, low PKCα expression identified cases with extremely poor outcome within the high-risk minimal residual disease (MRD) stratum, their incidence of relapse being of 69% vs. 15% in the high PKCα levels group. In a multivariate analysis adjusting for main prognostic features, PKCα proved to be an independent prognostic factor related to incidence of relapse. Very high risk patients within the high-risk MRD stratum, identified by PKCα expression, could be proposed for experimental therapeutic protocols.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170630PMC
http://dx.doi.org/10.18632/oncotarget.2062DOI Listing
July 2014

Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age cohorts.

Haematologica 2013 Nov 28;98(11):1702-10. Epub 2013 May 28.

or

The outcome of children and adults with acute lymphoblastic leukemia is markedly different. Since there is limited information on the distribution of clinico-biological variables in different age cohorts, we analyzed 5202 patients with acute lymphoblastic leukemia enrolled in the Italian multicenter AIEOP and GIMEMA protocols and stratified them in nine age cohorts. The highest prevalence of acute lymphoblastic leukemia was observed in children, although a second peak was recorded from the 4(th) decade onwards. Interestingly, the lowest incidence was found in females between 14-40 years. Immunophenotypic characterization showed a B-lineage in 85.8% of patients: a pro-B stage, associated with MLL/AF4 positivity, was more frequent in patients between 10-50 years. T-lineage leukemia (14.2%) was rare among small children and increased in patients aged 10-40 years. The prevalence of the BCR/ABL1 rearrangement increased progressively with age starting from the cohort of patients 10-14 years old and was present in 52.7% of cases in the 6th decade. Similarly, the MLL/AF4 rearrangement constantly increased up to the 5(th) decade, while the ETV6/RUNX1 rearrangement disappeared from the age of 30 onwards. This study shows that acute lymphoblastic leukemia in adolescents and young adults is characterized by a male prevalence, higher percentage of T-lineage cases, an increase of poor prognostic molecular markers with aging compared to cases in children, and conclusively quantified the progressive increase of BCR/ABL(+) cases with age, which are potentially manageable by targeted therapies.
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http://dx.doi.org/10.3324/haematol.2012.080432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815170PMC
November 2013

The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia.

PLoS One 2013 8;8(3):e58424. Epub 2013 Mar 8.

Oncology, Nerviano Medical Sciences, Nerviano, Milano, Italy.

CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592825PMC
September 2013

Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.

Blood 2010 Feb 24;115(5):1006-17. Epub 2009 Nov 24.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways.
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http://dx.doi.org/10.1182/blood-2009-08-235408DOI Listing
February 2010