Genetics and epigenetics in myeloid neoplasms
Genetic profiling for hematological malignancies means chasing a moving target. Only few years ago, leukaemias were stratified based on karyotye abnormalities. However, in recent years the knowledge of molecular genetics in haematology has increased significantly, something that offers new clinical opportunities. It has now been shown that gene expression, mutations and other genetic and epigenetic abnormalities also have diagnostic, prognostic and therapeutic implications. The aim of our group is to apply our research into three distinct haematological diseases: chronic myelomonocytic leukaemia, myelodisplastic syndromes and myeloproliferative neoplasms (PV, ET, PMF and CML), to finding better tools for diagnosis and prognosis stratification and to achieving an individual targeted therapies (personalized medicine).
We mainly focus our scientific interests on the following research areas:
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by features from both myelodysplastic syndromes and myeloproliferative neoplasms with median overall survival of 20 months and 15-30% of progression to acute myeloid leukemia (AML). The WHO and the French-American-Bristish Co-operative Leukaemia Group (FAB) stratifies CMML into two subsets based on blast count (CMML-1 and CMML-2) or leukocyte count (MD-CMML and MP-CMML), respectively. Nowadays there is still doubt whether these variants represent different clinical-biological entities or whether they are expression stages of the same entity. Clonal cytogenetic abnormalities are found in 20-30% of patients. The most frequently mutated genes are TET2, ASXL1, SRSF2, RUNX1 and CBL. The aim of our studies is to characterize 1) type, frequency and prognostic impact of mutations and cytogenetic alterations detected by SNP-arrays in patients with low risk CMML and 2) epigenetic changes (DNA methylation and miRNAs expression). These studies may provide information about the way gene expression deregulation contributes to leukaemogenesis in CMML and it may also help to determinate alterations that correlate with CMML subsets and aggressive variants of this disorder.
The classification and prognosis of the group of diseases termed Myelodisplastic Sindromes (MDS) depend on the blast count, number of cytopenias and cytogenetic data. Chromosomal abnormalities can be only detected in 50% of patients. For this reason, the detection of an aberrant methylation pattern for MDS or a common mutation gene profile may be useful for the diagnosis of this hematologic malignancy. Additionally, the detection of a characteristic methylation pattern or mutations in genes involved in epigenetic regulation could be associated with response to hypomethylating agents, allowing the election of a more personalized and dose-adjusted treatment that adapts to the characteristics of each patient. This knowledge will also contribute to a better understanding of MDS biology, to a better stratification of the prognosis of these patients (especially in the heterogeneous group of normal karyotype), which would also help with the selection of the most appropriate treatment for each of them. The detection of recurrent patterns of methylation will also allow us to identify new tumor suppressor genes.
Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of BCR-ABL fusion gene which give place a protein with a high tyrosine kinase (TK) activity. The first-line treatments for CML are TKI (Ex. Imatinib), which allow the achievement of cytogenetic and molecular response in most of the patients in chronic phase. However, some patients do not respond to this treatment or lose their initial response. The aim of our studies is to determine if we can find any genetic marker at diagnosis of CML that could explain patient’s toxicity to TKI or could differentiate which patients will achieve molecular response (hOCT1 expression, isoforms types, polymorphisms, and mutations). We also want to find a technique with higher sensitivity than QRT-PCR suitable for discontinuation treatment studies (Ex. dPCR)
BCR-ABL negative classic myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders may undergo phenotypic shifts, and may specifically evolve into secondary myelofibrosis (MF) or acute myeloid leukemia (AML). Discovery of the JAK2V617F mutation in the MPNs has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. We study several genomic changes (JAK2V617F mutations status and allele burden, SNP arrays and other gene mutational analysis) to try to associate them with cytological subtypes, laboratory parameters, clinical complications and probability of transformation either to MF or to AML.
Dra. Montse Arnan
Department of Clínical Hematology (MDS and AML group). ICO – Duran i Reynals, Hospitalet.
Dra. Conxa Boqué
Department of Clínical Hematology (MPN group). ICO – Duran i Reynals, Hospitalet.
Dra. Cristalina Fernandez
Department of Clínical Hematology (MPN group). ICO – Josep Trueta, Girona.
Dra. Rosa Coll
Department of Clínical Hematology (MDS and AML group). ICO – Josep Trueta, Girona.
Clonality analysis by HUMARA assay in Spanish females with essential thrombocythemia and polycythemia vera.Haematologica Feb 2005, 90 (2) 259-61.
Association of JAK2 mutation status and cytogenetic abnormalities at diagnosis in myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms.Am. J. Clin. Pathol. Apr 2012, 137 (4) 677-8. More information
Calreticulin mutations are not present in patients with myeloproliferative chronic myelomonocytic leukemia.Ann. Hematol. May 2015, 94 (5) 869-71. Epub 22 Nov 2014More information
Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features.Oncotarget 29 Jul 2016, . Epub 29 Jul 2016
Retrospective study to stablish a relationship between identified polymorphisms and imatinib intolerance or treatment response
|Project leader:||Lurdes Zamora|
Patrones de metilación en pacientes con SMD de alto riego y LMA secundaria a SMD tratados con fármacos hipometilantes según el protocolo del Grupo CETLAM SMD-alto riesgo <75 años
|Project leader:||Lurdes Zamora|
Estudio de los patrones de metilación en pacientes con Síndromes Mielodisplásicos (SMD) y Leucemia Mieloblástica Aguda secundaria a SMD tratados con fármacos hipometilantes versus tratamiento estándar.
|Project leader:||Lurdes Zamora|