SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations.

To elucidate whether tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI-resistant chronic myeloid leukemia patients with 250K single nucleotide polymorphism arrays. From 20 patients, matched serial samples of pretreatment and TKI resistance time points were available. Eleven of the 45 TKI-resistant patients had mutations of BCR-ABL1, including 2 T315I mutations. Besides known TKI resistance-associated genomic lesions, such as duplication of the BCR-ABL1 gene (n = 8) and trisomy 8 (n = 3), recurrent submicroscopic alterations, including acquired uniparental disomy, were detectable on chromosomes 1, 8, 9, 17, 19, and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in 3 patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI-induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity.

Lingual fat at autopsy.

OBJECTIVES/HYPOTHESIS: Obesity as measured by body mass index (BMI) has been shown to correlate with incidence and severity of sleep disordered breathing (SDB), but the actual mechanism underlying this relationship has not been defined. Pharyngeal obstruction from posterior displacement of a large, fat laden tongue is one mechanism that may explain this link. The objective of this study is to characterize the fat content within the tongue and then to determine whether tongue weight and percent of fat correlate with BMI and other metrics of obesity. STUDY DESIGN: This is a cross-sectional anatomic study performed at autopsy in 121 consecutive medical examiner cases. METHODS: Tongues were harvested, weighed, and sectioned. A standardized photograph was taken of each tongue in the midsagittal plane. The image was imported into ImageJ (NIH) and then digitally analyzed to estimate fat distribution and percent within the tongue. The measurements were divided into age and sex subsets and then examined for correlation with height, weight, BMI, organ weight, and abdominal subcutaneous fat thickness. RESULTS: This study includes data from 88 males, 27 females, and 6 children. The average tongue weight for males was 99 g, range 71 to 143 g; for females, 79 g, range 51 to 135 g; and for children, (mean age 4 yr) 38 g, range 15 to 81 g. Tongue weight correlated with BMI (r = 0.6, P < .0001). Percent of fat in the posterior tongue averaged 30 +/- 12% and correlated with BMI (r = 0.5, P < .0001) for both men and women. Percent of fat in the anterior tongue averaged 10 +/- 5% and correlated with BMI for males (P < .001). Anterior tongue fat percent did not correlate with BMI in females. CONCLUSION: Increase in tongue weight and percentage of fat, and therefore tongue volume, may explain why patients with weight gain have higher rates of SDB. Tongue weight, fat, and volume may also correlate with and explain Mallampati grades.