Genomic profile of chronic myelogenous leukemia: Imbalances associated with disease progression

Abstract

The expression of the chimeric BCR/ABL1 fusion gene resulting from t(9;22)(q34;q11) in chronic myelogenous leukemia (CML) is necessary for malignant transformation, but not sufficient to maintain disease progression. The appearance of various chromosomal and molecular alterations in the accelerated and terminal phase of CML is well documented, but evidence for causal relationship is largely lacking. We carried out a genome wide screening at a resolution of 1 Mb of 54 samples at different stages of CML together with 12 CML cell lines and found that disease progression is accompanied by a spectrum of recurrent genome imbalances. Among the most frequent are losses at 1p36, 5q21, 9p21, and 9q34 and gains at 1q, 8q24, 9q34, 16p, and 22q11, all of which were located with higher precision within the genome than previously possible. These genome imbalances are unique to CML cases with clinically manifested or suspected accelerated/blast stage alike, but not seen in chronic phase samples. Previously unrecognized cryptic imbalances occurring within the Ph-chromosome were also detected, although further scrutiny is required to pin-point gene involvement and seek association with disease features. Importantly, some of these imbalances were seen in the CD34(+) cells but not in the whole BM samples of patients in accelerated phase. Taken together, these findings highlight the potential of screening CD34(+) cells for genome wide imbalances associated with disease progression. Finally, the numerous single copy number variations recorded, many unique to this cohort of patients, raise the possible association of genome polymorphism and CML.

Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy

“…In chronic myeloid leukemia patients, specific chromosomal alterations, losses and gains were unique to cases with clinically manifested or suspected accelerated/blast stage. 18 To our knowledge, this is the first study showing an aCGH pattern for patients with aUPD involving part of or the entire HLA region. The technique also revealed constitutive or de-novo microdeletions or gains at 6p21 in four of the six patients.…”

Copy Number Variants: Distribution in Patients with Coronary Atherosclerosis

“…Sex mis-matched reference DNA Both male and female DnA was purchased from Promega UK (Promega, Southampton, UK). the DnA represented a mixture derived from six unrelated disease-free individuals of the same sex, but of unknown ethnic origin, medical history and age (2).…”

“…All procedures were performed as described previously by Brazma et al, (2007) (2). in brief, following hybridization slides were scanned at 10 µm resolution in a two-channel laser scanner -GenePix 4100B (MDS Analytical Technologies, USA), using GenePix v.6 software generating image (.tiff) and spot analysis (.gpr) files.…”

“…limits were calculated for any spot beyond which a deviation of the FR from unity could be considered amplified or deleted. This technique allowed us to compare genome profiles with varying quality in multiple patients' samples (2).…”

Multiple sub-microscopic genomic lesions are a universal feature of chronic myeloid leukaemia at diagnosis

“…Brazma et al 4 used a bacterial artificial chromosome array with a much lower resolution (1 Mb) and discovered 14 common cryptic abnormalities in CML blast crisis samples that were rare in chronic phase. In a comparison between Ph-positive acute lymphoblastic leukaemia and CML, Mullighan et al 5 used a higher-resolution 250 k SNP array and observed up to 8 CNAs per patient (range 0-8) in a cohort of 23 chronic phase CML samples, but no recurrent aberrations were detected and the authors did not specify whether samples had been taken at diagnosis or later in chronic phase.…”