RESUMO
Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic stem cells characterized by the aberrant production and uncontrolled proliferation of mature granulocytes with normal cell differentiation. The Philadelphia (Ph) chromosome resulting from reciprocal translocation between chromosomes 9 and 22 is the main genetic molecular hallmark of CML seen in more than 90% of the patients. However, about 5-10% of CML patients show a variant genetic rearrangement, involving one or more chromosomes in addition to 9 and 22. Herein, we describe the results of hematological, cytogenetic, fluorescence in situ hybridization (FISH), and high-end molecular analysis in a 77-year-old man diagnosed with CML. The combination of conventional cytogenetic analysis along with metaphase FISH and whole chromosomal paint revealed a novel cryptic variant chromosomal rearrangement involving 9q34, 22q11.2, and 5q22, resulting in ins(9;22) and t(5;22). At the molecular level, using PCR, myeloid NGS panels, and whole transcriptome analyses, we showed that this complex rearrangement indeed resulted in the formation of the BCR::ABL1 e13a2 major fusion transcript. No additional somatic mutations or kinase domain mutations were identified, thereby suggesting that the current case is indeed genetically homogeneous. This study provided strong evidence to support the idea that insertion-derived BCR::ABL1 fusions often involve complex chromosomal abnormalities that are overlooked by conventional cytogenetics but can be identified by a combination of conventional, molecular cytogenetics, and high-end NGS studies.
