Francesc Solé - Academia.edu (original) (raw)

Papers by Francesc Solé

Research paper thumbnail of Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

Cancer genetics and cytogenetics, 2004

... Author Contact Information , E-mail The Corresponding Author , a , b , Isabel Granada c , Lur... more ... Author Contact Information , E-mail The Corresponding Author , a , b , Isabel Granada c , LurdesZamora a , Blanca ... f Servei d'Hematologia Clíínica, Hospital del Mar–IMAS, Barcelona, Spain. ... 3. JL Laï, M. Zandecki, JY Mary, F. Bernardi, V. Izydorczyk, M. Flactif, P. Morel, JP Jouet ...

Research paper thumbnail of Characterization of New Aberrations in 25 Splenic Marginal Zone B-Cell Lymphomas (SMZBCL) Using Spectral Karyotyping Technique (SKY)

Blood, Nov 16, 2005

BACKGROUND/INTRODUCTION Splenic Marginal Zone B-Cell Lymphoma (SMZBCL) is a specific low grade sm... more BACKGROUND/INTRODUCTION Splenic Marginal Zone B-Cell Lymphoma (SMZBCL) is a specific low grade small B-cell lymphoma described by the World Health Organization (WHO). SMZBCL has distinct features from other B-cell malignancies, but few studies include a large series of patients. Previous reports suggest that SMZBCL constitute a genetically heterogeneous disease being 7q22-q32 deletions and gains of 3q the most frequent cytogenetic aberrations. Karyotypes are often complex and difficult to interpret. Other recurrent chromosomes involved are 1 and 8. Nevertheless, at this cytogenetic level few studies have been reported and the possible chromosome markers are not still well defined. OBJECTIVES The aim of this study is to define karyotypes from patients with SMZBCL by SKY technique. PATIENTS AND METHODS Among a series of 138 patients we have selected 25 with undefined karyotype. The diagnosis of SMZBCL was confirmed by morphology, histology, phenotype and clinical data. All samples were obtained from peripheral blood, bone marrow or spleen. The current SKY protocol has been used with minor modifications to improve the spectral image. We analyzed a minimum of ten metaphases per karyotype and they were described according to the International System for Human Cytogenetic Nomenclature (ISCN). RESULTS All the studied karyotypes were complex with chromosome aberrations which, in most cases, were not fully characterized by G-banding. SKY has allowed to refine chromosomal aberrations and revealed new translocations which were not defined by conventional cytogenetics. In nine cases, the karyotype remained unchanged after SKY analysis and in the remaining cases, new aberrations were described. We observed that the most common involved chromosomes in translocations were 14, 6, 13 and 17. CONCLUSIONS SKY provides a useful complementary technique to routine conventional cytogenetics in the analysis of lymphomas with complex karyotypes. SKY will permit to reveal new translocations associated with SMZBCL. The following new translocations involving 14q32 were found: t(1;14)(p22;q32), t(1;14)(q21;q32), t(9;14)(?;q32), t(9;14)(9pter-9p21::14q32-14q11::9p24-9qter), t(9;14)(p21;q32), t(10;14)(p12;q32), t(14;19)(q32;q13).

Research paper thumbnail of Contribution of cytogenetics and in situ hybridization to the study of monoclonal gammopathies of undetermined significance

Cancer genetics and cytogenetics, 2002

Monoclonal gammopathies of undetermined significance (MGUS) are characterized by the presence of ... more Monoclonal gammopathies of undetermined significance (MGUS) are characterized by the presence of a monoclonal protein in serum in quite asymptomatic patients. Ten to 33% of MGUS patients eventually will develop overt multiple myeloma, but no single laboratory test exists that can predict changes toward a malignant evolution. The aim of the present study was to apply conventional cytogenetics, the MAC (morphology, antibody, chromosome) method and fluorescence in situ hybridization (FISH) techniques in a series of 50 MGUS patients and 4 "smoldering" multiple myeloma patients to test the usefulness of their approaches as predictive methodologies. All patients studied by conventional cytogenetics presented a normal karyotype independent of the culture conditions used. The MAC method revealed that all mitotic cells showing a normal karyotype were positive for anti-MOP7 or anti-CD3 in 12 patients studied. In addition, two of them presented a numerical abnormality detected by FISH. Using a FISH technique with direct labeled centromeric probes for chromosomes 3, 7, 11, and 18 we showed a numerical abnormality in eight of 35 patients (23%) with a normal karyotype. The common occurrence of MGUS and the fact that they may evolve toward lymphoproliferative disorders displays the importance of being able to identify laboratory results that are capable of predicting the evolution of these patients. In the literature, patients who presented an IgA peak of immunoglobulin type have been associated with a higher risk of evolving to a malignant condition. Our study shows the correlation of MGUS patients who presented monosomy 18 with the presence of an immunoglobulin peak of the IgA type. Prospective follow-up is needed to evaluate the clinical value of monosomy 18 as a predictive factor for defining a high risk of malignant transformation in MGUS patients.

Research paper thumbnail of Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7

Leukemia, Feb 17, 2020

Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and interm... more Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with −7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with −7). Patients with del(7q) or −7 had similar demographic and diseaserelated characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in −7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with −7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated −7 or del(7q).

Research paper thumbnail of Supplementary Figure S2 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

PDF file 132K, Validation of gene expression analysis results by qRT-PCR

Research paper thumbnail of Supplementary Figure S1 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

PDF file 122K, Absolute lymphocyte counts in peripheral blood from MALD1 individuals over time

Research paper thumbnail of Incidence, Clinical Associations, and Co-Mutation Patterns of UBA1 Mutations in MDS

Research paper thumbnail of 16. International working group recommendations for the implementation of optical genome mapping in Hematologic Malignancies

Research paper thumbnail of 3135 – CD34+CD19-CD22+ B-Cell Progenitors Might Underlie Phenotypic Escape in Patients Treated with CD19-DIRECTED Therapies

Experimental Hematology

Preleukemic CD34 1 CD19 2 CD22 1 immature progenitors may underlie phenotypic escape in patients ... more Preleukemic CD34 1 CD19 2 CD22 1 immature progenitors may underlie phenotypic escape in patients treated with CD19-directed immunotherapies. The study contributes to identifying patients with BALL at risk of failure of CD19targeted therapy. CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with BALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34 1 CD22 1 CD19 2 (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34 1 CD19 2 CD22 1 cells are found in diagnostic and relapsed bone marrow samples of~70% of patients with BALL , and their frequency increases twofold in patients with BALL in CR after CD19 CAR T-cell therapy. The median of CD34 1 CD19 2 CD22 1 cells before treatment was threefold higher in patients in whom BALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34 1 CD19 2 CD22 1 cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34 1 CD19 2 CD22 1 progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19 2 relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with BALL during CD19-targeted therapy is encouraged.

Research paper thumbnail of CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies

Blood

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphobl... more CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed imm...

Research paper thumbnail of Guidelines and Quality Assurance for Acquired Cytogenetics

A common European framework for quality assessment for banded chromosome studies and molecular cy... more A common European framework for quality assessment for banded chromosome studies and molecular cytogenetic investigations of acquired abnormalities.

Research paper thumbnail of Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL)

Leukemia Research, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of ALL-257: Unraveling IKZF1 Deletion Therapeutic Vulnerabilities in Adult B-Cell Precursor Acute Lymphoblastic Leukemia

Clinical Lymphoma Myeloma and Leukemia, 2020

Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor... more Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP ALL) in children and adults. Objective To analyze the frequency and prognostic impact of IKZF1 deletions in adult BCP ALL patients. To identify the IKZF1 gene expression signature to find patients with different deletion isoforms and therapeutic opportunities. Patients and methods MLPA or SNP array samples of 151 (109 Ph-negative and 42 Ph+) adult BCP ALL patients treated with MRD-oriented protocols from the PETHEMA Group. RNAseq was performed in 48 of them (27 Ph-negative and 21 Ph+). Results Median age was 40 [15–72] years. Ph+ patients showed older age (52 [20;72] vs. 36 [15;68] years, p 1.5 in RNAseq data analysis, we identified a robust IKZF1 deletion gene expression profile. This resulted in 119 significantly upregulated genes after multi-comparison adjustment (i.e. CCND1, LAMA3, SLC2A9, SNAI1, LDHC, CD34, ID3, CDH2, MAF) and 39 downregulated genes (i.e. ROBO1, HES6, KREMEN1, DHCR24, ABHD15). Downregulated genes were involved in Slit/Robo/EMT, Notch, Wnt/beta-catenin, and glucose and fatty acid metabolism pathways, while upregulated genes were involved in focal adhesion, ROS homeostasis, histone modification, anaerobic metabolism, stem cell quiescence, and IL-6/STAT pathways. A significant number of dysregulated gene targets of chemotherapeutic agents (retinoic acid, doxorubicin, cisplatin, gemcitabine) and targeted therapies, such as FAKi, ERKi, BCL2i, mTORi, JAKi, BRKi, EGFRi and CDKi, were identified. Conclusions Adult BCP ALL patients with IKZF1 partial gene deletions showed poor prognosis. Gene expression analysis enables the identification of potentially targetable lesions. Funding Supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI14/01971); 2017 SGR288 (GRC) Generalitat de Catalunya; and support from CERCA Programme/Generalitat de Catalunya, Fundacio Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation.

Research paper thumbnail of Genome Wide Analysis of 41 Mycosis Fungoides Tumor Stage Using Array Comparative Genomic Hybridization Technology

Blood, 2008

Introduction : Primary cutaneous T cell lymphomas (CTCL) represent 70% of all cutaneous lymphomas... more Introduction : Primary cutaneous T cell lymphomas (CTCL) represent 70% of all cutaneous lymphomas. The most frequent is mycosis fungoides/Sézary syndrome (MF/ SS). In this entity, few high resolution cytogenetic studies have been performed. Our aim was to analyze chromosomal abnormalities in MF tumoral stage by array comparative genomic hybridization (ArrayCGH) and to describe potential candidate genes related to this disease. Patients and methods : Forty-one patients (22 males/19 females) with MF tumor stage were included from centres collaborating in the EORTC Cutaneous Lymphoma Group. DNA was extracted from frozen tissues containing more than 70% of tumor cells. ArrayCGH tecnhology was performed to detect genomic imbalances (gains/losses) using the Humane Genome CGH Microarray Kit 44B (Agilent Techologies). This array consists on 44.000 oligo probes of 60 bp covering all the human genome with a mean resolution of 50–100 Kb. CGH-Analytics 3.2.25 and InSilicoArray CGH (http://isac...

Research paper thumbnail of Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

Blood Advances, 2019

Key PointsWe report here the findings from the first known MDS genome-wide association study and ... more Key PointsWe report here the findings from the first known MDS genome-wide association study and meta-analysis identifying 8 unique loci. Genes harboring suggested MDS-associated loci, including EYA2, are innate immune regulators and may have clinical and biological relevance.

Research paper thumbnail of Therapy-Related MDS Can be Separated into Different Risk-Groups According to Tools for Classification and Prognostication of Primary MDS

Blood, 2018

The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) ... more The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) into one subgroup assuming all tMDS had the same poor prognosis. We have put together a database including 2032 patients with a diagnosis of tMDS from several different IWG centers and the MDS clinical research consortium. With the idea of developing an individual scoring system for tMDS, we decided to start by optimizing the cytogenetic part of the IPSSR. First, we did an extensive review of karyotypes. Finally, 1245 patients had complete data and correct ISCN formula to be used for score development. We could show regarding karyotypes there are very limited differences between primary and tMDS. Mainly the distribution of risk groups differs with complex occurring more (37%) and normal karyotypes occurring less frequent, although still accounting for 30%. There are few exceptions that are relatively special for tMDS, like translocations including 11q23. A few karyotypes are less frequen...

Research paper thumbnail of The Complete Mutatome and Clonal Architecture of Del(5q)

Blood, 2015

Cytogenetic abnormalities are found in around half of MDS patients (pts) and have both clinical i... more Cytogenetic abnormalities are found in around half of MDS patients (pts) and have both clinical impact and may be subtype-defining, e.g. in 5q-syndrome. Interstitial deletion of the long arm of chr.5 [del(5q)] is the most common aberration (almost 20% of cases with abnormal cytogenetics). Del(5q) is heterogeneous, occurring as a sole abnormality or in combination, with the deleted region often truncated within or extended and/or beyond the CDR boundaries. Isolated del(5q) is frequently shorter and confers a more favorable prognosis with regard to survival and lenalidomide (LEN) responsiveness, while del(5q) in the context of a complex karyotype (CK) imparts a poor prognosis. In addition to chromosomal lesions, somatic mutations can contribute to the pathogenesis of MDS, including del(5q). We theorized that recognition of molecular defects in MDS with del(5q) may clarify the pathogenic mechanisms behind this lesion and help explain the clinical heterogeneity. We analyzed 225 pts with...

Research paper thumbnail of Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group

Blood, 2009

1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the p... more 1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective: To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods: Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overal...

Research paper thumbnail of Genomic Characterization of Paired Diagnosis and Relapse Samples from Adult Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Blood, 2016

Background & Objective: Acute Lymphoblastic Leukemia (ALL) is an aggressive neoplasia characteriz... more Background & Objective: Acute Lymphoblastic Leukemia (ALL) is an aggressive neoplasia characterized by a high genetic heterogeneity both at diagnosis and at relapse. Due to the high incidence of relapse in adults and the dismal prognosis beyond recurrence, diagnosis and relapse samples of adult ALL patients were carefully analyzed in order to identify genetic alterations related with drug resistance and disease progression. Patients & Methods: Paired diagnosis-relapse bone marrow samples from 5 adult B-cell precursor ALL (B-ALL) patients were analyzed (Ph+ ALL [n=2], normal karyotype [n=1], t(1;19)(q23;p13) [n=1] and t(8;13)(p21-22;q12) [n=1]). Copy Number Alterations (CNA) were studied with Multiplex Ligation-dependent Probe Amplification (MLPA, kits P-335 and P-202 from MRC-Holland, Amsterdam, Netherlands) and Affymetrix CytoScan HD arrays (Affymetrix, Santa Clara, USA). In the array analyses, only the CNA that encompassed at least 25 markers were considered significant. Results: ...

Research paper thumbnail of The poor prognosis of low hypodiploidy in adults with B‐cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients

British Journal of Haematology, 2019

SummaryThe prognostic significance of low‐hypodiploidy has not been extensively evaluated in mini... more SummaryThe prognostic significance of low‐hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)‐oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5‐year cumulative incidence of relapse (CIR) of low‐hypodiploid B‐cell precursor (BCP)‐ALL was significantly higher than that of high‐hypodiploids (52% vs. 12%, P = 0.013). Low‐hypodiploid BCP‐ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5‐year CIR (17% vs. 66%, P = 0.090) than low‐hypodiploids aged >35 years. Older adults and elderly low‐hypodiploid BCP‐ALL patients show dismal prognosis although achieving an end‐induction good MRD response.

Research paper thumbnail of Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

Cancer genetics and cytogenetics, 2004

... Author Contact Information , E-mail The Corresponding Author , a , b , Isabel Granada c , Lur... more ... Author Contact Information , E-mail The Corresponding Author , a , b , Isabel Granada c , LurdesZamora a , Blanca ... f Servei d&amp;amp;amp;#x27;Hematologia Clíínica, Hospital del Mar–IMAS, Barcelona, Spain. ... 3. JL Laï, M. Zandecki, JY Mary, F. Bernardi, V. Izydorczyk, M. Flactif, P. Morel, JP Jouet ...

Research paper thumbnail of Characterization of New Aberrations in 25 Splenic Marginal Zone B-Cell Lymphomas (SMZBCL) Using Spectral Karyotyping Technique (SKY)

Blood, Nov 16, 2005

BACKGROUND/INTRODUCTION Splenic Marginal Zone B-Cell Lymphoma (SMZBCL) is a specific low grade sm... more BACKGROUND/INTRODUCTION Splenic Marginal Zone B-Cell Lymphoma (SMZBCL) is a specific low grade small B-cell lymphoma described by the World Health Organization (WHO). SMZBCL has distinct features from other B-cell malignancies, but few studies include a large series of patients. Previous reports suggest that SMZBCL constitute a genetically heterogeneous disease being 7q22-q32 deletions and gains of 3q the most frequent cytogenetic aberrations. Karyotypes are often complex and difficult to interpret. Other recurrent chromosomes involved are 1 and 8. Nevertheless, at this cytogenetic level few studies have been reported and the possible chromosome markers are not still well defined. OBJECTIVES The aim of this study is to define karyotypes from patients with SMZBCL by SKY technique. PATIENTS AND METHODS Among a series of 138 patients we have selected 25 with undefined karyotype. The diagnosis of SMZBCL was confirmed by morphology, histology, phenotype and clinical data. All samples were obtained from peripheral blood, bone marrow or spleen. The current SKY protocol has been used with minor modifications to improve the spectral image. We analyzed a minimum of ten metaphases per karyotype and they were described according to the International System for Human Cytogenetic Nomenclature (ISCN). RESULTS All the studied karyotypes were complex with chromosome aberrations which, in most cases, were not fully characterized by G-banding. SKY has allowed to refine chromosomal aberrations and revealed new translocations which were not defined by conventional cytogenetics. In nine cases, the karyotype remained unchanged after SKY analysis and in the remaining cases, new aberrations were described. We observed that the most common involved chromosomes in translocations were 14, 6, 13 and 17. CONCLUSIONS SKY provides a useful complementary technique to routine conventional cytogenetics in the analysis of lymphomas with complex karyotypes. SKY will permit to reveal new translocations associated with SMZBCL. The following new translocations involving 14q32 were found: t(1;14)(p22;q32), t(1;14)(q21;q32), t(9;14)(?;q32), t(9;14)(9pter-9p21::14q32-14q11::9p24-9qter), t(9;14)(p21;q32), t(10;14)(p12;q32), t(14;19)(q32;q13).

Research paper thumbnail of Contribution of cytogenetics and in situ hybridization to the study of monoclonal gammopathies of undetermined significance

Cancer genetics and cytogenetics, 2002

Monoclonal gammopathies of undetermined significance (MGUS) are characterized by the presence of ... more Monoclonal gammopathies of undetermined significance (MGUS) are characterized by the presence of a monoclonal protein in serum in quite asymptomatic patients. Ten to 33% of MGUS patients eventually will develop overt multiple myeloma, but no single laboratory test exists that can predict changes toward a malignant evolution. The aim of the present study was to apply conventional cytogenetics, the MAC (morphology, antibody, chromosome) method and fluorescence in situ hybridization (FISH) techniques in a series of 50 MGUS patients and 4 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;smoldering&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; multiple myeloma patients to test the usefulness of their approaches as predictive methodologies. All patients studied by conventional cytogenetics presented a normal karyotype independent of the culture conditions used. The MAC method revealed that all mitotic cells showing a normal karyotype were positive for anti-MOP7 or anti-CD3 in 12 patients studied. In addition, two of them presented a numerical abnormality detected by FISH. Using a FISH technique with direct labeled centromeric probes for chromosomes 3, 7, 11, and 18 we showed a numerical abnormality in eight of 35 patients (23%) with a normal karyotype. The common occurrence of MGUS and the fact that they may evolve toward lymphoproliferative disorders displays the importance of being able to identify laboratory results that are capable of predicting the evolution of these patients. In the literature, patients who presented an IgA peak of immunoglobulin type have been associated with a higher risk of evolving to a malignant condition. Our study shows the correlation of MGUS patients who presented monosomy 18 with the presence of an immunoglobulin peak of the IgA type. Prospective follow-up is needed to evaluate the clinical value of monosomy 18 as a predictive factor for defining a high risk of malignant transformation in MGUS patients.

Research paper thumbnail of Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7

Leukemia, Feb 17, 2020

Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and interm... more Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with −7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with −7). Patients with del(7q) or −7 had similar demographic and diseaserelated characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in −7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with −7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated −7 or del(7q).

Research paper thumbnail of Supplementary Figure S2 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

PDF file 132K, Validation of gene expression analysis results by qRT-PCR

Research paper thumbnail of Supplementary Figure S1 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

PDF file 122K, Absolute lymphocyte counts in peripheral blood from MALD1 individuals over time

Research paper thumbnail of Incidence, Clinical Associations, and Co-Mutation Patterns of UBA1 Mutations in MDS

Research paper thumbnail of 16. International working group recommendations for the implementation of optical genome mapping in Hematologic Malignancies

Research paper thumbnail of 3135 – CD34+CD19-CD22+ B-Cell Progenitors Might Underlie Phenotypic Escape in Patients Treated with CD19-DIRECTED Therapies

Experimental Hematology

Preleukemic CD34 1 CD19 2 CD22 1 immature progenitors may underlie phenotypic escape in patients ... more Preleukemic CD34 1 CD19 2 CD22 1 immature progenitors may underlie phenotypic escape in patients treated with CD19-directed immunotherapies. The study contributes to identifying patients with BALL at risk of failure of CD19targeted therapy. CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with BALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34 1 CD22 1 CD19 2 (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34 1 CD19 2 CD22 1 cells are found in diagnostic and relapsed bone marrow samples of~70% of patients with BALL , and their frequency increases twofold in patients with BALL in CR after CD19 CAR T-cell therapy. The median of CD34 1 CD19 2 CD22 1 cells before treatment was threefold higher in patients in whom BALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34 1 CD19 2 CD22 1 cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34 1 CD19 2 CD22 1 progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19 2 relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with BALL during CD19-targeted therapy is encouraged.

Research paper thumbnail of CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies

Blood

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphobl... more CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed imm...

Research paper thumbnail of Guidelines and Quality Assurance for Acquired Cytogenetics

A common European framework for quality assessment for banded chromosome studies and molecular cy... more A common European framework for quality assessment for banded chromosome studies and molecular cytogenetic investigations of acquired abnormalities.

Research paper thumbnail of Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL)

Leukemia Research, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Research paper thumbnail of ALL-257: Unraveling IKZF1 Deletion Therapeutic Vulnerabilities in Adult B-Cell Precursor Acute Lymphoblastic Leukemia

Clinical Lymphoma Myeloma and Leukemia, 2020

Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor... more Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP ALL) in children and adults. Objective To analyze the frequency and prognostic impact of IKZF1 deletions in adult BCP ALL patients. To identify the IKZF1 gene expression signature to find patients with different deletion isoforms and therapeutic opportunities. Patients and methods MLPA or SNP array samples of 151 (109 Ph-negative and 42 Ph+) adult BCP ALL patients treated with MRD-oriented protocols from the PETHEMA Group. RNAseq was performed in 48 of them (27 Ph-negative and 21 Ph+). Results Median age was 40 [15–72] years. Ph+ patients showed older age (52 [20;72] vs. 36 [15;68] years, p 1.5 in RNAseq data analysis, we identified a robust IKZF1 deletion gene expression profile. This resulted in 119 significantly upregulated genes after multi-comparison adjustment (i.e. CCND1, LAMA3, SLC2A9, SNAI1, LDHC, CD34, ID3, CDH2, MAF) and 39 downregulated genes (i.e. ROBO1, HES6, KREMEN1, DHCR24, ABHD15). Downregulated genes were involved in Slit/Robo/EMT, Notch, Wnt/beta-catenin, and glucose and fatty acid metabolism pathways, while upregulated genes were involved in focal adhesion, ROS homeostasis, histone modification, anaerobic metabolism, stem cell quiescence, and IL-6/STAT pathways. A significant number of dysregulated gene targets of chemotherapeutic agents (retinoic acid, doxorubicin, cisplatin, gemcitabine) and targeted therapies, such as FAKi, ERKi, BCL2i, mTORi, JAKi, BRKi, EGFRi and CDKi, were identified. Conclusions Adult BCP ALL patients with IKZF1 partial gene deletions showed poor prognosis. Gene expression analysis enables the identification of potentially targetable lesions. Funding Supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI14/01971); 2017 SGR288 (GRC) Generalitat de Catalunya; and support from CERCA Programme/Generalitat de Catalunya, Fundacio Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation.

Research paper thumbnail of Genome Wide Analysis of 41 Mycosis Fungoides Tumor Stage Using Array Comparative Genomic Hybridization Technology

Blood, 2008

Introduction : Primary cutaneous T cell lymphomas (CTCL) represent 70% of all cutaneous lymphomas... more Introduction : Primary cutaneous T cell lymphomas (CTCL) represent 70% of all cutaneous lymphomas. The most frequent is mycosis fungoides/Sézary syndrome (MF/ SS). In this entity, few high resolution cytogenetic studies have been performed. Our aim was to analyze chromosomal abnormalities in MF tumoral stage by array comparative genomic hybridization (ArrayCGH) and to describe potential candidate genes related to this disease. Patients and methods : Forty-one patients (22 males/19 females) with MF tumor stage were included from centres collaborating in the EORTC Cutaneous Lymphoma Group. DNA was extracted from frozen tissues containing more than 70% of tumor cells. ArrayCGH tecnhology was performed to detect genomic imbalances (gains/losses) using the Humane Genome CGH Microarray Kit 44B (Agilent Techologies). This array consists on 44.000 oligo probes of 60 bp covering all the human genome with a mean resolution of 50–100 Kb. CGH-Analytics 3.2.25 and InSilicoArray CGH (http://isac...

Research paper thumbnail of Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

Blood Advances, 2019

Key PointsWe report here the findings from the first known MDS genome-wide association study and ... more Key PointsWe report here the findings from the first known MDS genome-wide association study and meta-analysis identifying 8 unique loci. Genes harboring suggested MDS-associated loci, including EYA2, are innate immune regulators and may have clinical and biological relevance.

Research paper thumbnail of Therapy-Related MDS Can be Separated into Different Risk-Groups According to Tools for Classification and Prognostication of Primary MDS

Blood, 2018

The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) ... more The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) into one subgroup assuming all tMDS had the same poor prognosis. We have put together a database including 2032 patients with a diagnosis of tMDS from several different IWG centers and the MDS clinical research consortium. With the idea of developing an individual scoring system for tMDS, we decided to start by optimizing the cytogenetic part of the IPSSR. First, we did an extensive review of karyotypes. Finally, 1245 patients had complete data and correct ISCN formula to be used for score development. We could show regarding karyotypes there are very limited differences between primary and tMDS. Mainly the distribution of risk groups differs with complex occurring more (37%) and normal karyotypes occurring less frequent, although still accounting for 30%. There are few exceptions that are relatively special for tMDS, like translocations including 11q23. A few karyotypes are less frequen...

Research paper thumbnail of The Complete Mutatome and Clonal Architecture of Del(5q)

Blood, 2015

Cytogenetic abnormalities are found in around half of MDS patients (pts) and have both clinical i... more Cytogenetic abnormalities are found in around half of MDS patients (pts) and have both clinical impact and may be subtype-defining, e.g. in 5q-syndrome. Interstitial deletion of the long arm of chr.5 [del(5q)] is the most common aberration (almost 20% of cases with abnormal cytogenetics). Del(5q) is heterogeneous, occurring as a sole abnormality or in combination, with the deleted region often truncated within or extended and/or beyond the CDR boundaries. Isolated del(5q) is frequently shorter and confers a more favorable prognosis with regard to survival and lenalidomide (LEN) responsiveness, while del(5q) in the context of a complex karyotype (CK) imparts a poor prognosis. In addition to chromosomal lesions, somatic mutations can contribute to the pathogenesis of MDS, including del(5q). We theorized that recognition of molecular defects in MDS with del(5q) may clarify the pathogenic mechanisms behind this lesion and help explain the clinical heterogeneity. We analyzed 225 pts with...

Research paper thumbnail of Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group

Blood, 2009

1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the p... more 1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective: To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods: Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overal...

Research paper thumbnail of Genomic Characterization of Paired Diagnosis and Relapse Samples from Adult Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Blood, 2016

Background & Objective: Acute Lymphoblastic Leukemia (ALL) is an aggressive neoplasia characteriz... more Background & Objective: Acute Lymphoblastic Leukemia (ALL) is an aggressive neoplasia characterized by a high genetic heterogeneity both at diagnosis and at relapse. Due to the high incidence of relapse in adults and the dismal prognosis beyond recurrence, diagnosis and relapse samples of adult ALL patients were carefully analyzed in order to identify genetic alterations related with drug resistance and disease progression. Patients & Methods: Paired diagnosis-relapse bone marrow samples from 5 adult B-cell precursor ALL (B-ALL) patients were analyzed (Ph+ ALL [n=2], normal karyotype [n=1], t(1;19)(q23;p13) [n=1] and t(8;13)(p21-22;q12) [n=1]). Copy Number Alterations (CNA) were studied with Multiplex Ligation-dependent Probe Amplification (MLPA, kits P-335 and P-202 from MRC-Holland, Amsterdam, Netherlands) and Affymetrix CytoScan HD arrays (Affymetrix, Santa Clara, USA). In the array analyses, only the CNA that encompassed at least 25 markers were considered significant. Results: ...

Research paper thumbnail of The poor prognosis of low hypodiploidy in adults with B‐cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients

British Journal of Haematology, 2019

SummaryThe prognostic significance of low‐hypodiploidy has not been extensively evaluated in mini... more SummaryThe prognostic significance of low‐hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)‐oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5‐year cumulative incidence of relapse (CIR) of low‐hypodiploid B‐cell precursor (BCP)‐ALL was significantly higher than that of high‐hypodiploids (52% vs. 12%, P = 0.013). Low‐hypodiploid BCP‐ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5‐year CIR (17% vs. 66%, P = 0.090) than low‐hypodiploids aged >35 years. Older adults and elderly low‐hypodiploid BCP‐ALL patients show dismal prognosis although achieving an end‐induction good MRD response.