Acute myeloid leukemia

Why classical cytogenetics still matters in acute myeloid leukemia

“…The underlying genetic features of NK AML could begin to be addressed when molecular genetic analyses emerged during the 1980s and 1990s. It was then shown that leukemiaassociated translocations/inversions result in rearrangements of genes located in the breakpoints, as first shown for the MYC gene in Burkitt lymphoma/leukemia with t(8;14)(q24;q32) and the ABL1 gene in chronic myeloid leukemia with t(9;22)(q34; q11) in 1982 [5,6], and that most of them lead to fusion genes encoding chimeric proteins with novel properties [2]. When reverse-transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) analyses began to be used routinely in a clinical setting during the 1990s, several NK AML cases were shown to be positive for various fusion genes by RT-PCR/FISH analyses but cytogenetically negative for the corresponding structural chromosome abnormalities.…”

“…Within just a few years, a large number of chromosomal aberrations were detected in AML, such as t(8;21)(q22;q22) [the first AML-specific translocation identified], inv(3) (q21q26), monosomy 5/del(5q), t(6;9)(p22;q34), monosomy 7/ del(7q), trisomy 8, t(15;17)(q24;q21), and complex karyotypes (CK), to name but a few. In parallel with the increasing number of AML-associated abnormalities reported in the following decade, it became apparent that many of them were associated with certain, sometimes characteristic, morphologic, immunophenotypic, and clinical features [2,3]. Today, identification of several specific chromosomal changes is essential for proper risk stratification, and, hence, for treatment decision.…”

“…Today, identification of several specific chromosomal changes is essential for proper risk stratification, and, hence, for treatment decision. For example, some aberrations in AML are associated with a favorable outcome, such as t(8;21) and inv(16), and others with a dismal prognosis, such as inv(3), CK, and monosomal karyotype (MK) [2,4].…”

“…Despite the obvious clinical importance of cytogenetic investigations of AML, it should be emphasized that they definitely have their shortcomings. For example, if chromosome morphology is poor, several important risk stratifying abnormalities may escape detection, such as inv(3) and inv(16) [2]. Furthermore, approximately half of all AML cases have a normal karyotype (NK), reflecting either dividing nonneoplastic cells outgrowing the leukemic clone in vitro or the presence of cryptic changes not identifiable by chromosome banding analysis.…”

“…When reverse-transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) analyses began to be used routinely in a clinical setting during the 1990s, several NK AML cases were shown to be positive for various fusion genes by RT-PCR/FISH analyses but cytogenetically negative for the corresponding structural chromosome abnormalities. Instead, the fusions were generated by other mechanisms, mostly cryptic insertions [2]. In order to avoid such false-negative cases, RT-PCR/FISH analyses became a complement to classical cytogenetics and are today also applied for rapid detection of abnormalities that affect therapy early on during induction, for example gemtuzumab ozogamycin treatment of t(8;21)-or inv (16)-positive AML cases [7] -FISH results for these abnormalities can, if prioritized, be available within 1-2 days.…”