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Published on: September 20, 2016
Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic
Tadayuki Akagi1, Lee-Yung Shih, Motohiro Kato
1Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA. tadayuki@staff.kanazawa-u.ac.jp
Abstract:
Acute promyelocytic leukemia (APL) is a hematopoietic malignant disease characterized by the chromosomal translocation t(15;17), resulting in the formation of the PML-RARA gene. Here, 47 t(15;17) APL samples were analyzed with high-density single-nucleotide polymorphism microarray (50-K and 250-K SNP-chips) using the new algorithm AsCNAR (allele-specific copy-number analysis using anonymous references). Copy-number-neutral loss of heterozygosity (CNN-LOH) was identified at chromosomes 10q (3 cases), 11p (3 cases), and 19q (1 case). Twenty-eight samples (60%) did not have an obvious alteration (normal-copy-number [NC] group). Nineteen samples (40%) showed either one or more genomic abnormalities: 8 samples (17%) had trisomy 8 either with or without an additional duplication, deletion, or CNN-LOH (+8 group); and 11 samples (23%) had genomic abnormalities without trisomy 8 (other abnormalities group). These chromosomal abnormalities were acquired somatic mutations. Interestingly, FLT3-ITD mutations (11/47 cases) occurred only in the group with no genomic alteration (NC group). Taken together, these results suggest that the pathway of development of APL differs in each group: FLT3-ITD, trisomy 8, and other genomic changes. Here, we showed for the first time hidden abnormalities and novel disease-related genomic changes in t(15;17) APL.
Insights
This study reveals novel genomic abnormalities in acute promyelocytic leukemia (APL) using SNP-chips. These findings suggest distinct developmental pathways for APL, including FLT3-ITD mutations and trisomy 8.
Area of Science:
- Hematology
- Genetics
- Oncology
Background:
- Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia.
- APL is defined by the specific chromosomal translocation t(15;17), leading to the PML-RARA fusion gene.
Purpose of the Study:
- To investigate genomic abnormalities in t(15;17) APL using high-density single-nucleotide polymorphism (SNP) microarrays.
- To identify novel genetic alterations and understand their role in APL pathogenesis.
Main Methods:
- Analysis of 47 t(15;17) APL samples using 50-K and 250-K SNP-chips.
- Application of the AsCNAR algorithm for allele-specific copy-number analysis.
- Categorization of samples based on genomic alterations: normal-copy-number (NC), trisomy 8 (+8), and other abnormalities.
Main Results:
- Copy-number-neutral loss of heterozygosity (CNN-LOH) was observed at chromosomes 10q, 11p, and 19q.
- 60% of samples showed no obvious genomic alterations (NC group).
- 40% of samples exhibited genomic abnormalities, including trisomy 8 (17%) and other alterations (23%).
- FLT3-ITD mutations were exclusively found in the NC group (11/47 cases).
Conclusions:
- The study identified previously unrecognized genomic abnormalities in t(15;17) APL.
- Distinct genetic profiles suggest different pathways in APL development, involving FLT3-ITD, trisomy 8, and other genomic changes.
- These findings contribute to a deeper understanding of APL pathogenesis.
