title: Deletions of immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia.
abstract: BACKGROUND
  Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric BCR/ABL1 fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the BCR/ABL1 fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood.
  
  
  RESULTS
  Here we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (IGH) and T cell receptor regions (TCR), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including IKZF1, HOXA7, CDKN2A/2B, MLLT3, IFNA/B, RNF38, PAX5, JMJD2C and PDCD1LG2 genes.
  
  
  CONCLUSIONS
  None of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at IGH and TCR regions appear to precede the loss of IKZF1 and/or p16 genes in CML indicating a possible involvement of RAG in these deletions.
authors.affiliation: UCL School of Medicine, Cancer Institute, Academic Haematology, Royal Free Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UK. e.nacheva@ucl.ac.uk
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Nacheva
authors.forename: Diana
authors.initials: D
authors.lastname: Brazma
authors.forename: Anna
authors.initials: A
authors.lastname: Virgili
authors.forename: Julie
authors.initials: J
authors.lastname: Howard-Reeves
authors.forename: Anastasios
authors.initials: A
authors.lastname: Chanalaris
authors.forename: Katya
authors.initials: K
authors.lastname: Gancheva
authors.forename: Margarita
authors.initials: M
authors.lastname: Apostolova
authors.forename: Mikel
authors.initials: M
authors.lastname: Valgañon
authors.forename: Helen
authors.initials: H
authors.lastname: Mazzullo
authors.forename: Colin
authors.initials: C
authors.lastname: Grace
mesh_terms: D001752:Blast Crisis / Q000235:genetics* / Q000276:immunology; D002897:Chromosomes, Human, Pair 7; D002899:Chromosomes, Human, Pair 9; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D019672:Genes, T-Cell Receptor; D019942:Genes, p16; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D017384:Sequence Deletion
chemical_list: C497239:IKZF1 protein, human; D007143:Immunoglobulin Heavy Chains; D051740:Ikaros Transcription Factor