Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highlyaltered genome: combined molecular and therapeutic studies
Por:
Farre, L, Sanz, G, Ruiz-Xiville, N, de Moura, MC, Martin-Tejera, JF, Goncalves-Ribeiro, S, Martinez-Iniesta, M, Calaf, M, Mosquera, JL, Martin-Subero, JI, Granada, I, Esteller, M, Domingo-Domenech, E, Climent, F, Villanueva, A and Sureda, A
Publicada:
1 jul 2021
Ahead of Print:
15 jul 2021
Resumen:
Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.CgP,kdcscidIl2,gtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.
Filiaciones:
Farre, L:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Sanz, G:
Bellvitge Biomed Res Inst, Catalan Inst Oncol, Dept Clin Hematol, Barcelona, Spain
:
Germans Trias & Pujol Hosp, Catalan Inst Oncol, Hematol Lab, Badalona 08916, Spain
Josep Carreras Leukaemia Res Inst, Canc & Leukemia Epigenet & Biol & Expt & Clin Hem, Barcelona 08916, Spain
de Moura, MC:
Josep Carreras Leukaemia Res Inst, Canc & Leukemia Epigenet & Biol & Expt & Clin Hem, Barcelona 08916, Spain
Martin-Tejera, JF:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Goncalves-Ribeiro, S:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Martinez-Iniesta, M:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Calaf, M:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Mosquera, JL:
Bellvitge Biomed Res Inst IDIBELL, IDIBELL Bioinformat Unit, Barcelona 08908, Spain
Martin-Subero, JI:
Univ Barcelona, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona 08036, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Spain
:
Germans Trias & Pujol Hosp, Catalan Inst Oncol, Hematol Lab, Badalona 08916, Spain
Josep Carreras Leukaemia Res Inst, Canc & Leukemia Epigenet & Biol & Expt & Clin Hem, Barcelona 08916, Spain
:
Josep Carreras Leukaemia Res Inst, Canc & Leukemia Epigenet & Biol & Expt & Clin Hem, Barcelona 08916, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Spain
Carlos III Inst Hlth, Ctr Invest Biomed Red Canc, Madrid 28029, Spain
Univ Barcelona, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona 08036, Spain
Domingo-Domenech, E:
Bellvitge Biomed Res Inst, Catalan Inst Oncol, Dept Clin Hematol, Barcelona, Spain
Climent, F:
Carlos III Inst Hlth, Ctr Invest Biomed Red Canc, Madrid 28029, Spain
Hosp Univ Bellvitge, Bellvitge Biomed Res Inst, Dept Pathol, Barcelona 08907, Spain
Villanueva, A:
Bellvitge Biomed Res Inst IDIBELL, Grp Chemoresistance & Predict Factors, Subprogram Canc Therapeut Resistance, Catalan Inst Oncol,Oncobell Program, Barcelona 08908, Spain
Xenopat SL, Business Bioincubator, Bellvitge Hlth Sci Campus, Barcelona 08907, Spain
Sureda, A:
Bellvitge Biomed Res Inst, Catalan Inst Oncol, Dept Clin Hematol, Barcelona, Spain
Green Published, gold
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