A novel t(9;22;11) translocation involving 11q24 in a patient with chronic myeloid leukemia: A case report Corrigendum in /10.3892/ol.2017.6875 (2024)

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Introduction

Of patients with chronic myeloid leukemia (CML),5–10% exhibit a Philadelphia (Ph) translocation variant involving≥1 chromosomes in addition to chromosomes 9 and 22 (1). Although the distribution of thebreakpoints exhibited a clearly nonrandom pattern in allchromosomes involved, there was a marked clustering in thechromosomal bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13,17p13, 17q21, 17q25, 19q13, 21q22, 22q12 and 22q13, suggesting thatthese regions may be particularly prone to breakage (2). The variant translocations affectadditional chromosomal regions, producing different diseasephenotypes. However, previous studies investigating ~100 cases ofvariant Ph chromosome translocations have not identified any impacton cytogenetic and molecular responses, or on patient outcome,compared with cases with a standard Ph chromosome (3,4). Themajority of three-way t(9;22;11) variants of CML involve the 11q13or 11p15 regions of chromosome 11 (1,5–11). The 11q24 region has not previouslybeen investigated in a three-way Ph variant.

Case presentation

A 22-year-old male was admitted to Chonbuk NationalUniversity Hospital (Jeonju, Korea) for the evaluation andmanagement of dizziness and severe leukocytosis in July 2011. Thepatient exhibited hepatosplenomegaly at admission without any otherknown chronic diseases. The initial complete blood count showedhemoglobin, 6.6 g/dl (normal range, 13–18 g/dl); platelets,492.0×109/l (normal range,150.0–450.0×109/l); and white blood cells,590.8×109/l (normal range, 4.8–10.8×109/l)with 8.0% myeloblasts, 71.6% neutrophils, 4.5% lymphocytes, 4.5%monocytes, 9.1% eosinophils and 2.3% basophils. Bone marrowaspiration and biopsy findings were indicative of chronic phase CMLwith 8.0% of myeloblasts demonstrating granulocytic hyperplasia.The karyotype of the patient was 46, XY, t(9;22;11)(q34;q11.2;q24)in all metaphase cells analyzed (Fig.1). A fluorescence in situ hybridization (FISH) analysisusing a commercial BCR/ABL fusion probe (AbbottMolecular Inc., DesPlaines, IL, USA) identified the following out of total 200interphase nuclei: 2 interphase nuclei with 1 single red signal(ABL1, 9q34), 1 single green signal (BCR, 22q11.2) and 2 fusionsignals; 197 nuclei with 2 single red signals, 2 single greensignals and 1 fusion signal; and 1 nucleus with 2 single reds, 1single green and 1 fusion signal (Fig.2A). MLL (11q23.1) break-apart FISH didn't show anyrearrangement. Multiplex reverse transcription-polymerase chainreaction (RT-PCR) analysis using the Multiplex Nested RT-PCRHemaVision® kit (cat. no. HV01-28N; DNA Diagnostics,Risskov, Denmark) was performed according to manufacturer'sinstructions, with 2 sequential nested PCR reactions using primersincluded in the kit, in order to detect translocations. RNA wasextracted from bone marrow samples using the High Pure RNAIsolation kit (Roche Diagnostics, Mannheim, Germany) as describedpreviously (12). A major BCR-ABLfusion transcript, type b3a2, was detected. Thus, the patient wasdiagnosed with chronic phase CML, and imatinib treatment wasreinitiated. The patient had demonstrated a complete hematologicalresponse for 1 year subsequent to the start of treatment, but thenstopped taking the medication. The patient was readmitted due toleukocytosis found in the laboratory test. Bone marrow findingsshowed that the initial diagnosis and the karyotype had notchanged. Additional FISH analysis using BCR/ABL dual fusion and MLLbreak-apart probes revealed that the Ph chromosome was derived froma simple variant t(9;22) via a one-step mechanism, that ABLproto-oncogene 1 (c-ABL; 9q34, red) had moved to a BCR (22q11.2,green) and formed a fusion (Ph), BCR had moved to 11q24, and 11q24moved to 9q34, whereas part of c-ABL remained, indicated by a redsignal (Fig. 2B).

In contrast to the 2 expected fusion signals onclassic Ph translocations, in the present study only 1 fusionsignal was revealed, indicating a one-step mechanism, such as asimultaneous break in 9q34, 11q24 and 22q11.2 followed by amismatched joining of the broken ends. Band 11q24 in this case hasnever been reported as a partner for Ph translocations.

Discussion

A three-way Ph translocation variant involving 11q24associated with CML has never been described. Variant Phtranslocations have been divided into simple variant translocationsinvolving chromosome 22 and another chromosome, and complex varianttranslocations involving chromosomes 9 and 22 and 1–3 otherchromosomes (2,13). Two different mechanisms are known togenerate variant three-way translocations, a one-step mechanism inwhich chromosomal breaks occur simultaneously on 3 differentchromosomes and a two-step mechanism involving 2 sequentialtranslocations in which a standard t(9;22) translocation isfollowed by a second translocation involving additional chromosomes(14–16). The case presented in the present studywas considered to be a simple variant translocation generated by aone-step mechanism. A variant translocation generated by a two-stepmechanism is similar to clonal evolution, thus this mechanism maybe associated with a poorer prognosis. The case of the presentstudy showed a one-step variant translocation clinically identicalto classic Ph translocations.

Variant translocations may possibly affect thecourse of the disease by altering the structure of the tyrosinekinase ligand binding site. Although numerous studies haveaddressed the possible effect of variant translocations on theclinical course of chronic phase CML, contradictory results havebeen reported (3,4,17).Previous studies have indicated that the clinical, prognostic andhematological features of types of CML exhibiting varianttranslocations are not distinct from types of CML exhibitingclassic translocations, but the majority of these studies werebased on a small series or literature reviews (2–4). Band11q24, as a variant translocation partner, is a novel region thathas not been investigated. Thus, the present study possessed noinformation on the clinical course or hematological features of CMLwith t(9;22;11) (q34;q11.2;q24). However, the patient of thepresent study experienced chronic phase CML twice with the samechromosomal abnormality, thus the clinical course between the firstdiagnosis and the relapse was compared. A three-way variantt(9;22;11) involving 11q24 was detected at the initial diagnosis,and the relapse samples indicated that the CML was in the chronicphase at the initial and relapse diagnoses. The clinical course ofthe patient was also similar prior and subsequent to relapse.

References