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MLL Rearrangment and EVI1 Deletion in BCR/ABL1 Positive Chronic Myeloid Leukemia

2013-12-01 19:50:07

Journal of the Association of Genetic Technologists; 2014 March; DOI:doi.org/10.5858/arpa.2012-0736-OA



Aleksandr Ivanov, Madina Sukhanova, Tracy Raul, Olesya Borinets, Wai Hui, Veena Aggarwal, Gordana Raca



Abstract



We present unusual cytogenetic findings in a 65-year-old female with blast phase (BC) of Philadelphia chromosome positive chronic myeloid leukemia (CML). Chromosome analysis revealed two related abnormal clones, one characterized by a t(9;22)(q34;q11.2), and the other showing a t(11;19)(q23;p13.1) in addition to the t(9;22)(q34;q11). Fluorescence in situ hybridization (FISH) testing confirmed that the t(11;19) involved the MLL gene on 11q23. High-density whole-genome SNP array analysis of leukemia cells showed a number of submicroscopic copy number abnormalities, including a deletion of the MECOM (MDS1 and EVI1 complex locus protein EVI1) gene at 3q26. Clinical course was aggressive, and the patient failed to respond to both imatinib and dasatinib despite the absence of resistance associated mutations in the BCR/ABL1 gene. To our knowledge, the combination of a t(9;22) with t(11;19)(q23;p13.1) has only been reported in one case, while a deletion of the EVI1 gene has never been reported in CML.



INTRODUCTION



Chronic myeloid leukemia (CML) is a clonal disorder of pluripotential stem cells (Fialkow et al., 1977). The disease arises as a consequence of a reciprocal translocation between chromosomes 9 and 22, (Rowley, 1973) resulting in a fusion of the BCR and ABL1 genes and expression of the constitutively active BCR-ABL1 protein tyrosine kinase (Westbrook, 1988). BCR-ABL1 is responsible for the leukemic phenotype, through the activation of multiple signaling pathways (Daley et al., 1990). The course of the disease is characteristically triphasic: a chronic phase (CP) lasting three to six years is followed by transformation to an accelerated phase (AP) and then a terminal blast crisis (BC) of short duration (Faderl et al., 1999; Sawyers, 1999). Continued cytogenetic monitoring of CML patients through phase progression showed that the leukogenic process in CML is of sequential clonal evolution. Genomic instability due to the BCR-ABL1 product leads to the continuous acquisition of new genetic (or epigenetic) alterations creating subclones with growth advantage that differentially affects disease progression (Kantarjian et al., 1988; Johansson et al., 2002). In CML, cytogenetic abnormalities in addition to the Philadelphia (Ph)–chromosome are not random; the most frequent are trisomy 8, additional Ph-chromosome, isochromosome (17q), and trisomy 19 (Johansson et al., 2002). Chromosomal abnormalities involving the mixed lineage leukemia (MLL) gene have rarely been reported concomitantly with the t(9;22)(q34;q11). The MLL gene, located on 11q23, is frequently rearranged in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (Thirman et al., 1993). The MLL abnormalities are also prevalent in therapy-related AML (t-AML) arising subsequent to treatment with topoisomerase inhibitors (Super et al., 1993). We present an uncommon occurrence of an MLL rearrangement due to a t(9;22)(q34;q11.2), in a CML clone from a 65-year-old female patient in BC. In addition to the t(9;22) and t(11;19), a submicroscopic deletion of the EVI1 gene was detected by high-density whole-genome DNA array testing. The combination of t(9;22) with t(11;19)(q23;p13.1) has only been reported once, and a deletion of the EVI1 locus has not been reported previously in CML. (Suzuki et al., 2004; Zámecˆnikova, 2011).



CASE REPORT



A 65-year-old woman presented to our hospital from an outside institution with a recent diagnosis of CML. Fluorescence in situ hybridization (FISH) testing had been performed previously, and it confirmed the presence of a BCR-ABL1 rearrangement. At the time of admission, the patient’s white blood cell count (WBC)
was 110.8 K/uL, hemoglobin concentration was 10.7 g/dL, platelet count was 434 K/uL, with a differential count of 1% myeloblasts, promyelocytes 2%, myelocytes 12%, metamyelocytes 12%, neutrophils 58%, basophils 7%, eosinophis 2%, lymphocytes 4% and monocytes 2%. There was no significant dysplasia in the granulocytic cells. The RBCs were normochromic, normocytic.



BM aspirate and biopsy showed a markedly hypercellular marrow (95% cellular) due to a proliferation of granulocytes, including immature, maturing and mature forms, as well as megakaryocytes. The fraction of myeloblasts did not appear to be significantly increased. Cytogenetic analysis revealed two abnormal clones, one characterized by a t(9;22)(q34;q11), and the other characterized by a t(11;19)(q23;p13.1) in addition to the t(9;22).



The patient failed to respond to imatinib as well as dasatinib, and she presented four months later with obvious clinical and morphologic signs of progression into a BC. The repeated bone marrow aspirate showed sheets of immature monocytoid cells. Cytochemical stains on the marrow aspirate smears showed that more than 90% of the cells strongly expressed the monocyte related non-specific esterase, alpha naphthyl butyrate esterase.



Flow cytometry revealed a uniform population of cells that expressed CD4, CD13, CD14, CD15, CD33, CD11b, HLA-DR and cMPO. There was no expression of CD34 and CD117. No mutations were detected in the ABL1 and NPM1 genes. In contrast, the bone marrow sample obtained at the time of the first admission showed no evidence of a population of immature monocytoid cells. The findings in the second sample were consistent with the diagnosis of a monocytic blast phase of CML. The final cytogenetic analysis showed predominance of cells with 46,XX,t(9;22)(q34;q11),t(11;19)(q23;p13.1) (17 out of 20 cells analyzed). The patient died due to refractory disease.



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