Chronic myeloid leukemia CML developed when a single, pleuripotential, haemotopoietic stem cells acquires a philadelphia (Ph) chromosome carring the BCR/ABL fusion gene, which confers on its progeny a proliferative advantage over normal haematopoietic element and thus allow the Ph-positive clone gradually to displace residual normal haematopoiesis.
The (Ph) chromosome, the most frequent cytogenetic abnormality present in human leukemias, is a derivative chromosome 22 arising as a consequence of a reciprocal translocation between the long arms of chromosomes 9 and 22. This rearrangement results in the formation of a chimeric BCR/ABL fusion gene on the derivative chromosome 22.
It was proposed that, in a subset of CML patients, the recombination event that generate an apparently reciprocal translocation can also produce large genomic deletion on chromosome 9q34. these deletions are large, span the translocation breakpoint, and occur at the same time of the Ph translocation.
CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. The poor prognosis associated with deletions is seen in patients treated with Imatinib, hydroxyurea, interferon or even stem cell transplantation.
9q34 has been a focus of attention as a site harboring tumor suppressor genes whose loss of function contributes to leukemia transformation of tumor progression.
FISH was performed for BCR/ABL genes and 9q34 deletion on chromosome 9 & 22 by using dual colour dual fusion probe and another probe directed at the arginonosuccinate synthetase (ASS) gene in a series of 20 patients diagnosed before as CML by S.FISH: - 20 (100%) patients were positive for D-FISH and 18 (90%) patients were positive for 9q34 deletion.
The presence of 9q34 deletions showed a significant direct correlation with TLC, LAP score and BCR/ABL. A significant invers correlation with haemoglobin and RBCs was reported.
The CML patients, 10 of them were treated by Glevic and the another 10 were treated by hydroxyurea. There was 6 cases with unfavorable outcome in the form of: blastic crisis, accelerated phases or died, all of them were 9q34 positive and 5/6 (83%) were taken Imatinib as treatment.
Diagnostic accuracy in chronic leukemias can be improved if traditional morphology and cytochemistry are supplemented with immunophenotyping and genotypic analysis. This multiparameter approach is of crucial importance for the management of patients as it enables the identification of leukemic syndromes with distinct biological features and response to treatment. The established relationship between malignancy and chromosomal changes has made cytogeneitc studies a significant part of a number of hematological disorders. It helps in the diagnosis, prognosis, monitoring and therapy.
FISH provides a rapid, quantitative method for the detection of cells with chromosome abnormalities in peripheral blood and bone marrow specimens using small amount of material which is particularly useful in hypocellular marrows and when aspiration is difficult with results independent of cell cycle status and representative of entire populations rather than restricted to cycling cells as is the case with routine cytogenetic analysis. FISH could detect MRD in specimens seemed normal by all standard morphological and cytogenetic criteria.
In conclusion, while FISH will not replace routine karyotypic analysis of material at presentation, it does provide a powerful and sensitive tool for monitoring the disease in patient with karyotypic abnormalities. Thus the detection of 9q34 deletion by FISH is very important since this deletion harbors tumor suppressor genes so this allows better understanding of the mechanism of leukemogenesis and for better stratification of treatment modalities. |
