CYTOGENETIC ABNORMALITIES IN ACUTE LEUKEMIA PATIENTS: RESULTS OF CONVENTIONAL CYTOGENETICS AND FLUORESCENT IN SITU HYBRIDIZATION ANALYSES
Yilmaz Z1,*, Sahin FI1, Kizilkilic E2, Karakus S3, ?zbek N4, Boga C2, ?zdogu H2
*Corresponding Author: Zerrin Yilmaz, MD, Baskent University Faculty of Medicine, Department of Medical Biology and Genetics, Kubilay Sokak No. 36, 06570 Maltepe, Ankara, Turkey; Tel.: +90-312-232-44-00/139; Fax: +90-312-232-39-12; E-mail: zerriny@baskent.edu.tr
page: 33

DISCUSSION

Chromosome rearrangements have been used to classify acute leukemia patients with different clinical outcomes [6]. Technological advances have led to important developments in diagnosis and treatment of hematological malignancies. Applications of FISH have enabled our understanding of the differences underlying the biology of the disease.

 The t(8;21) translocations and chromosome 16 inversions identify patients with a comparatively good prognosis. We identified a t(8;21) translocation in one patient who was diagnosed as AML-M2. The t(8;21) is associated with AML-M2 [7]. The t(8;21) and inv(16) both affect the AML1/CBFa-CBFb transcription factor complex. Both rearrangements are present in approximately 15% of cases. We also observed a chromosome 16 inversion in AML patients.

The t(15;17)(q22:q11.21) is the cytogenetic marker of acute promyelocytic leukemia (APL), (AML-M3). The t(15;17) probe showed the translocation in nine of the AML-M3 patients. However, we did not detect the trans?location by conventional cytogenetics. According to the previous report by Grimwade et al. [8], among APL patients, 15% have been reported to be cytogenetically negative regarding the translocation, i.e., 6% have cryptic rearrangements due to insertions or complex transloca?tions, and 9% are the result of cytogenetic failures. These results indicate that not all M3 patients have t(15;17) as the cytogenetic rearrangement.

The t(9;22) was observed in 11 patients, of whom six were ALL and five were AML. By conventional cyto?genetics, the Philadelphia (Ph) chromosome has been reported to be detected in 20 to 25% of adult ALL cases [9]. Chromosome banding analysis has been recommended as the first genetic test as it screens both t(9;22) and additional chromosome rearrangements. To assess the trans?location with a higher sensitivity in the translocation negative cases, FISH and reverse transcription-polymerase chain reaction (RT-PCR) analysis methods have been developed [9,10].

 The t(9;22) (BCR-ABL) translocation in childhood ALL subjects has a lower incidence than adults with a 2 to 4% frequency, depending on the detection method used. In a study of 1,322 children with ALL, it has been re?ported that, although Ph positive patients achieved complete remission after induction therapy, they were more likely to relapse when compared with the Ph negative group [11]. Although it has a negative impact on ALL prognosis, nearly all patients, regardless of the fusion, achieve remission after induction therapy [10].

The structural abnormality of the 11q23 band and the MLL gene involved in the region is a recurrent chromosome abnormality in acute leukemia [12]. More than 50 chromosomal loci and 30 genes have been identified as MLL partners. Twenty-five percent of MLL rearrangements are missed by conventional cytogenetic analysis [12]. In this study, we detected MLL rearrangement in only one AML and one pediatric ALL patient.

We detected some of the structural and numerical chromosome abnormalities by conventional cytogenetics. In other cases, FISH was another method that enabled us to clarify the chromosome rearrangements. In his review, Bagg explains the reason for false negative results in two ways [13]. First, the translocations are truly cryptic, and second, the results may have a technical basis. Both reasons highlight the value of molecular genetic studies as a complement to, but not instead of, conventional cyto?genetics [13].

Cytogenetic analysis needs dividing cells. The meta?phases obtained are sometimes not of good metaphase quality to enable karyotype analysis. Standard karyotyping may miss some of the subtle chromosome abnormalities [14]. Fluorescent in situ hybridization overcomes the pitfalls associated with conventional cytogenetic methods, since it can be performed on metaphase or interphase preparations. The FISH procedure is useful mainly around the time of initial diagnosis or during relapse [14]. When abnormal cell levels decrease, such as in remission or minimal residual disease follow-up, FISH is not useful as the sensitivity is one positive cell in 100 normal cells [14].

In our study, FISH has been useful in detecting cyto?genetic rearrangements in samples in which we were not able to detect chromosome abnormalities by conventional cytogenetics or in which we could not obtain good quality metaphases. Although, the new techniques including molecular cytogenetics seem to be useful in leukemia diagnosis; conventional cytogenetics is still the method of choice.




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