Subject(s)
Cell Transdifferentiation , Immunotherapy/adverse effects , Lymphoma, Mantle-Cell/therapy , Neoplasms, Second Primary/etiology , Sarcoma/etiology , Adenine/administration & dosage , Adenine/adverse effects , Adenine/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Transdifferentiation/genetics , Cell Transdifferentiation/immunology , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Cellular Reprogramming/physiology , Combined Modality Therapy , Epigenesis, Genetic/physiology , Epigenome/immunology , Gene Rearrangement , Genes, Immunoglobulin Heavy Chain/genetics , Humans , Immunotherapy/methods , Lymph Nodes/pathology , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/immunology , Neoplasms, Second Primary/diagnosis , Piperidines/administration & dosage , Piperidines/adverse effects , Receptors, Antigen, T-Cell/therapeutic use , Rituximab/administration & dosage , Rituximab/adverse effects , Sarcoma/genetics , Sarcoma/immunology , Sarcoma/pathology , Transplantation, Autologous/adverse effects , Tumor Cells, CulturedABSTRACT
Transformation of follicular lymphoma (FL) into B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is rare and results in greatly increased aggressiveness of clinical course. Here we present extensive molecular analysis of this unusual transformation, including immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole-exome sequencing (WES) of the patient's FL, B-ALL/LBL, and normal cells. Although FL showed marked somatic hypermutation (SHM) of the Ig genes, SHM appeared to be even more extensive in B-ALL/LBL. Cytogenetically, at least three translocations were identified in the B-ALL/LBL involving the BCL2, BCL6, and MYC genes; two of these, the BCL6 and BCL2 gene rearrangements, were already seen at the FL stage. WES identified 751 single-nucleotide variants with high allelic burden in the patient's cells, with the vast majority (575) present exclusively at the B-ALL/LBL stage. Of note, a TAF3 gene mutation was shared by normal, FL, and B-ALL/LBL tissue. A KMT2D nonsense mutation was identified in both FL and B-ALL/LBL and therefore may have contributed directly to lymphomagenesis. Mutations in KDM6A, SMARCA4, CBX1, and JMY were specific to the B-ALL/LBL stage, possibly contributing to the B-ALL/LBL transformation. Functionally, these identified mutations may lead to dysregulation of DNA repair, transcription, and cell differentiation. Thus, these genetic changes, together with the identified chromosomal translocations, may have contributed to lymphoma development and progression. Our findings may improve the mechanistic understanding of the FL-B-ALL/LBL transformation and may have therapeutic implications for this aggressive disease.
Subject(s)
Biomarkers, Tumor , Cell Transformation, Neoplastic/genetics , Lymphoma, Follicular/genetics , Lymphoma, Follicular/pathology , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adult , Alleles , Amino Acid Sequence , Base Sequence , Biopsy , Chromobox Protein Homolog 5 , Diagnostic Imaging/methods , Disease Progression , Gene Rearrangement , Histones/metabolism , Humans , Immunoglobulin Heavy Chains/genetics , Immunohistochemistry , Immunophenotyping , In Situ Hybridization, Fluorescence , Lymphoma, Follicular/therapy , Male , Methylation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Exome SequencingABSTRACT
Trisomy 8 is a common cytogenetic abnormality in myeloid malignancies. It can also be present constitutionally and is associated with a wide range of phenotypes. We report a case of a 20-year-old woman with acute myelogenous leukemia associated with the 11q23/MLL translocation who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a healthy, unrelated 26-year-old female. Cytogenetics on a bone marrow biopsy and aspirate performed 71 days after transplant to evaluate pancytopenia identified trisomy 8 in 6 of 7 cells examined. The bone marrow was hypocellular but normal by morphology and flow cytometry. Fluorescent in situ hybridization (FISH) for the original 11q23/MLL translocation was negative. Chimerism analysis using multiplex polymerase chain reaction to amplify an informative short tandem repeat demonstrated 97% donor cells. These findings were confirmed by repeat bone marrow biopsies at Day 110 after transplant and 1 year after transplant. With resolution of comorbid illness, the patient's peripheral blood counts recovered and remained normal at 1 year after HSCT. FISH analysis of a cryopreserved sample of the donor graft showed trisomy 8 in 120 of 200 cells examined. This represents the first reported case of a person with constitutional trisomy 8 mosaicism serving as a stem cell donor. The case illustrates the importance of identifying donor-derived constitutional abnormalities to avoid the assumption that these cytogenetic abnormalities after HSCT are representative of malignant disease.
