Oligonucleotide Array CGH Studies Identify Specific Genomic Imbalances in Chronic Myelomonocytic Leukemia with Normal Karyotype
M Nassiri, M Miravalle, M Czader. Indiana University School of Medicine, Indianapolis, IN
Background: Chronic myelomonocytic leukemia (CMML) is a hematopoietic malignancy with hybrid myeloproliferative and myelodysplastic features, which is still defined by clinicopathological parameters and represents a heterogeneous group with variable outcomes. Most of our knowledge about genetic basis of this disease is based on conventional cytogenetics, which offered limited insight in the pathogenesis of this neoplasm. Only 40% of patients with CMML shows karyotypic abnormalities including trisomy 8 and monosomy 7/del(7q). Genes most frequently affected include RUNX1, ASXL1, TET2 and RAS. To further investigate the biological diversity of CMML, we studied genomic DNA with oligonucleotide array CGH (oaCGH).
Design: We studied bone marrow samples from 10 patients with CMML including 7 males and 3 females. Seven patients presented with CMML-1 and 3 with CMML-2 (defined by WHO criteria). Two cases showed WBC below 13x109/L. Cytogenetic results were available in all of the patients with 8 patients showing normal karyotype. All cases were negative for BCR-ABL1 translocation. Microarray studies were performed using Agilent human oaCGH microarrays (105k) containing probes for more than 99000 sequences. Normal pooled female genomic DNA was used as reference. Arrays were scanned on an Agilent microarray scanner, and analyzed by Agilent software.
Results: Using intervals based analysis with z-score aberration algorithm various gain and loss regions which were not detected by conventional cytogenetic. CMML-1 group showed gain of 16 p13.3 in all cases, however only one case in CMML-2 group showed similar gain. No consistent abnormalities were seen in CMML-2 cases with normal karyotype. Cases with WBC >13x109/L showed consistent gain in 1p36.13, 7p22.3, 7q11.23, 17q25.3, 20q13.33 and loss of 8p11.21. In contrast all cases with WBC <13x109/L showed gain of 6p21.33 and 6q27. Several potential gene candidates included in these regions are (ATP6V1G2, NFKBIL1, DACT-2 and SMOC2). Additional genetic abnormalities were shared in subsets of cases with WBC>13x109/L. None of those changes were present in cases with WBC<13x109/L.
Conclusions: We have identified novel genomic gain and loss regions in CMML by high density oaCGH, some of which were localized to few genes loci. Gains involving chromosomes 16 and 6 might be more common than previously reported. The correlation with biological function and clinical significance of specific genes in these regions are being investigated.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 164, Tuesday Afternoon