Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 1, Num. 2, 2005, pp. 108-110

Journal of Cancer Research and Therapeutics, Vol. 1, No. 2, April-June, 2005, pp. 108-110

Brief Communications

A three way complex translocation (4;9;22) in two patients with chronic myelocytic leukemia

Sheth FrennyJ, Sheth JayeshJ, Verhest Alain

FRIGE (Foundation for Research in Genetics and Endocrinology) Genetic Centre, 20/1, Bima Nagar, Satellite, Ahmedabad-380 015
Correspondence Address:FRIGE (Foundation for Research in Genetics and Endocrinology) Genetic Centre, 20/1, Bima Nagar, Satellite, Ahmedabad-380 015, jshethad1@sancharnet.in

Code Number: cr05022

Abstract

INTRODUCTION

Chronic myeloid leukemia (CML) is a clinical myeloproliferative disorder involving the pluripotent stem cell. The hallmark of CML is the Philadelphia chromosome (Ph′), which results from translocation between chromosomes 9 and 22 where c-abl protooncogene is translocated from chromosome 9 to the break point cluster region on chromosome 22.[1] It may also arise from complex rearrangements involving three or more chromosomes.[2],[3] In 70-80% of CML cases the development of the blastic or acute phase involves additional chromosome abnormalities, such as an isochromosome for the long arm of #17, trisomy 19, occasionally trisomy 8 and a missing Y.[2] In CML, translocations other than the standard reciprocal translocation (9;22) occur in about 5 to 8% of cases. [2],[3],[4],[5] It is generally accepted that in CML the relationship and significance of such secondary chromosome abnormalities to the evolution of the disease is unclear. The evolution of prognostic features in a limited number of CMLs with classical or variant Ph′rearrangements gave controversial results [6] owing to the limited number of well documented cases with long-term clinical and cytogenetic follow up.[7]

In the present study we report about the clinical, cytogenetic and molecular findings of two patients with complex translocation involving chromosome 4, 9 and 22.

Case Report

Two cases presented here have been diagnosed clinically and hematologically as CML. One of the patient, aged 42 years attended Genetic Centre on January 1997 to undergo cytogenetic study from bone marrow. The study showed presence of Philadelphia chromosome in all metaphases and total WBC count was 256 x 10 ⁹ /l. The differential count was: neutrophils 40%, lymphocytes 8%, monocytes 3%, eosinophil 1%, blast 15%, band 16%, promyelocytes 12%, myelocytes 12% and metamyelocytes 12%. The patient had splenomegaly with marked granulocytic hyperplasia and an increased number of megakaryocytes.

He was on a-interferon for 9 months and the hematological picture showed 8 percent premature cells with WBC count of 9.6x10 ⁹ /l. Karyotypic picture showed presence of Philadelphia chromosome in all cells. Proband came after three and half years for follow-up in an accelerated state when WBC count was 72.8x10 ⁹ /l and differential count was: neutrophils 39%, lymphocyte 4%, eosinophil 4%, basophils 10%, monocytes 3%, band 15%, promyelocytes 3%, myelocytes 8% and metamyelocytes 6%. Cytogenetic study from bone marrow has revealed complex translocation involving chromosome t(4;9;22) (q25;q34;q11) with an additional Philadelphia and marker chromosome [Figure - 1].

The second patient was diagnosed with CML in October 2000, with total WBC count of 144x10 ⁹ /l. Differential count was: neutrophils 36%, lymphocytes 12%, eosinophil 6%, basophils 3%, band 5%, myelocytes 35% and metamyelocytes 3%. He had moderate splenomegaly with mild hepatomegaly. Bone marrow was hypercellular with severe myeloid hyperplasia and an adequate number of megakaryocytes and LAP score was 2, which was suggestive of chronic phase of CML. Cytogenetic analysis from bone marrow revealed complex translocation t(4;9;22)(q25;q34;q11). Since he could not afford a-interferon he was treated with hydroxyurea. After seven courses of chemotherapy the patient came again for cytogenetic study from bone marrow. It has shown the same cytogenetic report with no evolution. Both patients are healthy after 3 to 5 years of initial diagnosis.

FISH analysis of the bcr/abl in case 1, produced 77% of double Ph′, 15% single rearrangement and 2% collocation in 100 interphase nuclei [Figure - 2].

Case 2 revealed 66.5% rearrangement, 5% collocation and 28.5% of the 200 nuclei with a normal distribution of the spots.

The painting of chromosome 9 is illustrated on [Figure - 3]A and B.

DISCUSSION

Involvement of chromosome 9 in Ph′ positive CML patients is well known. The common molecular event underlying classical, masked and variant Ph′ translocations is the production of the BCR/ABL fusion gene. Evolution of prognostic features in a limited number of CMLs with classical or variant Ph′rearrangements gave controversial results.[6] Some studies have indicated that the secondary anomalies in chromosome may be associated with the acute nature of the disease.[8] However as observed in our patients, the complex translocation occurred in the context of chronic phase of CML and their clinical significance is unclear. Clonal evolution resulting from the additional numerical or structural chromosomal abnormalities in patients with CML is very important to note because 50% patients enter an accelerated phase after about 3 years and eventual transformation to acute leukemia.[5],[9] Such abnormal clonal evolution resulting from the complex translocation as observed in the present cases and those reported by others is not known. Tharapel et al[7] noted that reciprocal translocations involving no loss or gain of the genetic material might not involve in abnormal clonal evolution and may have better prognostication than those with unbalanced karyotypic changes. Similar observation made by Hild [10] suggested that chromosomal abnormalities observed in addition to the Ph′chromosome at the time of initial diagnosis may not be associated with the poor prognosis. Though the specific clonal evolution has not been identified.

FISH analysis of these two cases showed double rearrangements involving complex reciprocal translocation though it is not possible to determine whether these represent abnormal clonal evolution or a unique, initial presentation of the variant Ph chromosome. But it is likely that the reciprocal translocation might display a benign effect on the evolution of the disease as opposed to the more deleterious nature of the unbalanced chromosome arrangement such as trisomy 1, trisomy 19 and iso (17q) which are seen in the blastic phase.[Figure - 4]

CONCLUSION

ACKNOWLEDGEMENT

References

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