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Indian Journal of Cancer, Vol. 45, No. 1, January-March, 2008, pp. 30-32 Case Report Three way translocation in a new variant of t(8;21) acute myeloid leukemia involving Xp22 Vundinti BR, Kerketta L, Madkaikar M, Jijina F, Ghosh K Institute of Immunohaematology (ICMR), 13th Floor, New Multistoryed Building, KEM Hospital Campus, Parel, Mumbai - 400 012, Maharashtra Code Number: cn08007 Abstract The t(8;21)(q22;q22) is one of the most frequent chromosomal abnormality associated with acute myeloid leukemia (AML) M2 sub type. The additional chromosomal abnormalities including structural and numerical are frequently reported with the translocation, t (8;21)(q22;q22). We report a case of AML-M2 with t(X;8;21)(p22;q22;q22) associated with loss of Y chromosome. Using a dual color fluorescence in situ hybridization (FISH) analysis with ETO and AML1 probes, we demonstrated an ETO/AML1 fusion signal on the derivative chromosome 8 and one ETO signal on derivative Chromosome Xp22. The patient did not respond to therapy and follow-up of cytogenetics revealed same chromosome abnormality. Hence, this three way translocation involving X chromosome might be associated with poor prognosis. Keywords: Acute myeloid leukemia, AML-M2, ETO/AML fusion, Xp22 Introduction The t(8;21) is one of the most frequent chromosomal abnormality associated with acute myeloid leukemia (AML) involves the AML1 (acute leukemia 1 also called RUNX1, core binding factor protein (CBF alpha) and PEBP2 alpha B) gene on Chromosome 21 and the ETO (eight-twenty one also MTG8) gene on Chromosome 8. [1] The t(8;21)(q22;q22) is associated with 12% of denovo AML cases and up to 40% in the AML subtype M2 of the French-American-British (FAB) classification. Furthermore, it is also reported in a small portion of M0, M1 and M4 AML patients. Clinically t(8;21) with AML usually shows some specific characteristics and has a good response to chemo therapy with a higher remission rate and a long median survival. [2] On the other hand, some patients also showed poor prognosis in AML with t(8;21) and the associated bad prognosis factors have not been strongly established to date. The t(8;21)(q22;q22) frequently associated with additional chromosomal aberrations and it is one of the most recurrent chromosomal abnormalities in AML. [3] Approximately 3% to 4% of AML associated with t(8;21) have variant translocations. [4] Some investigators have reported a favorable outcome for patients with AML with variant t(8;21), [5] similar to patients with classical t(8;21) but others have reported that patients who have AML with variant t(8;21) have a worse prognosis. [6] Here we report a case of AML(M2) with a 45,t(X;8;21)(p22;q22;q22),-Y karyotype as a variant chromosomal abnormality.Case Report A-30-year-old male, farmer by occupation, presented with fever and pain in joints for one month and progressive weakness and fatigability. He was a non-smoker and a non-consumer of alcohol. Complete blood count values were as follows; hemoglobin (Hb), 11.4g/dL; mean corpuscular volume (MCV), 102.2 fl; white blood cells (WBC),0.015X10 9 /L; and platelets, 0.095X10 9 /L. Bone marrow aspirate was hypercellular with 56% blasts and majority are medium large sized with 0-1 nucleoli and Aur rods. All stages of erythroid maturation, reduction in megakaryocytes and presence of iron stores were observed. The patient was diagnosed as AML-M2 according to the French-American -British classification. The patient′s thyroid function was normal; vitamin B12 and folate levels were within the normal range. Tests for antinuclear factor and HIV antibody were negative. The patient was treated with 7 + 3 regime Ara-C and Mitoxanthrone. The BM aspiration after one month showed remission and cytogenetic findings were unchanged. Patient died after two months in remission from remittent relapse.Immunophenotype Immunophenotyping of leukemia blasts was done using fluorescein isothiocyanate and phycoerythrin-conjugated monoclonal antibodies (Becton Dickinson, Franklin Lakes, NJ). Antibodies against the following antigens were used; CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD13, CD14, CD15, CD19, CD33, CD34, CMPO and HLA-DR. Less than 20% positivity was considered a negative result. The blasts showed positivity with CD13 (84%) CD19 (66%), CD33 (61%), CD34 (65%), HLA-DR (71%) and MPO stain positivity. Based on these findings and using a European Group for the Immunological characterization of acute leukemias (EGIC) criteria, the patient was diagnosed with AML-M2.Cytogenetics Cytogenetic analysis of unstimulated bone marrow cell was performed at the time of diagnosis and after one month of treatment using direct harvest and harvest after 24h-culture. Metaphase chromosomes were GTG-banded and karyotyped according to ISCN 2005. Chromosomal analysis revealed mosaic karyotype with 45,X,t(X;8)(p22;q22)-Y (17) and 46,XY [8] [Figure - 1]. Fluorescence in situ hybridization (FISH) was performed according to standard procedure using AML1 and ETO dual color dual fusion probe (Vysis, Germany). FISH analysis revealed AML1/ETO fusion on Chromosome 8q22 region and the ETO (red) gene translocated to Chromosome Xp22 [Figure - 2]. The combination of FISH and G-banding chromosome analysis of the patient was 45,X,t(X;21;8)(p22.1;q22;q22),-Y karyotype. Discussion The t(8; 21)(q22; q22) is most commonly reported chromosomal abnormality in ANLL. This anomaly is seen in 15% of all the AML with differentiations (M2) and some cases of AML (M4). [1] Patients with t(8;21) reported to have a favorable prognosis with uniformly high complete remission rate, they respond well to high dose Ara-C containing regime. [2] The additional chromosome abnormalities were frequently reported in t(8;21) cases. The additional numerical changes and structural changes reported to be two third and one third cases respectively. [3] The deletions of Chromosomes 7q and 9q in t(8;21) associated with good prognosis. Recently Huang et al , [7] reported four cases with three way translocation involving t(8;21) and these variant translocation had good response as in typical t(8;21) cases. Others also reported variant translocation in t(8;21) patients and shown good prognosis. [8] In our case, chromosome analysis in combination with GTG-banding and FISH revealed three way translocation t(X;21;8)(p22;q22;q22), where ETO gene is translocated to Xp22 region. It is presumed to be Xp22.1 region translocated to Chromosome 21 and AML1 translocated to 8q22. The Xp22 translocation to 21q22 has been reported in one case of AML. [9] Though molecular cytogenetic evaluation of Xp22.2 was not possible, to the best of our knowledge this is the first case of translocation between Xp22 and 8q22 in AML-M2. The Xp22 region contain PRDX4 gene, which is one of six peroxiredoxin-family genes that are highly conserved in eukaryotes and prokaryotes and are ubiquitously expressed. Peroxiredoxin genes exhibit thioredoxin-dependent peroxidase activity and have been implicated in a number of other other cellular functions such as cell proliferation and differentiation. PRDX4 plays a regulatory role in the activation of the transcription factor NF-kappa B and is significantly down regulated in acute promyelocytic leukemia. [9] This is the first case of antioxidant enzyme gene involved through translocation in leukemia. The loss of Y chromosome in t(8;21) have been reported to be associated with an aggressive clinical and intermediate prognosis. [10] Recently KIT and internal tandem duplications (ITD) of FLT3 is considered to be predicting poor prognosis in AML. However FLT3 mutations were ruled out in our case. The patient was not responding to therapy and died after two months. Since the patient had loss of Y chromosome and had three way translocation involving Xp22.1, the variant t(8;21) with X chromosome might be poor prognostic indicator. It is also essential to see the loss of Y chromosome in variant translocation for better management of the disease. However molecular biological studies are important to understand the molecular mechanism of variant translocations in leukemia. References
Copyright 2008 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn08007f2.jpg] [cn08007f1.jpg] |
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