Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

Abstract

<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric <it>BCR/ABL1 </it>fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the <it>BCR/ABL1 </it>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.</p> <p>Results</p> <p>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 (<it>IGH</it>) and T cell receptor regions (<it>TCR</it>), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including <it>IKZF1</it>, <it>HOXA7</it>, <it>CDKN2A/2B</it>, <it>MLLT3</it>, <it>IFNA/B</it>, <it>RNF38</it>, <it>PAX5</it>, <it>JMJD2C </it>and <it>PDCD1LG2 </it>genes.</p> <p>Conclusions</p> <p>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 <it>IGH </it>and <it>TCR </it>regions appear to precede the loss of <it>IKZF1 </it>and/or <it>p16 </it>genes in CML indicating a possible involvement of RAG in these deletions.</p