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Insertion of chromosome 11 in chromosome 4 resulting in a 5′MLL-3′AF4 fusion gene in a case of adult acute lymphoblastic leukemia

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Abstract

We report on a 69-year-old woman with B-lineage acute lymphoblastic leukemia. Cytogenetic studies at diagnosis with R banding showed an insertion, ins(4;11)(q21;q13q23). Fluorescence in situ hybridization (FISH) with whole chromosome painting probes confirmed the insertion of chromosome 11 material into chromosome 4. FISH using the MLL probe showed the translocation of the 5′ end of MLL into chromosome 4. Since the 5′MLL-3′AF4 fusion transcript was detected by a reverse transcriptase polymerase chain reaction, we concluded that the insertion of part of chromosome 11 split the AF4 gene in two, resulting in the presence of the 5′MLL-3′AF4 fusion gene on the der(4) instead of the der(11), as commonly observed. Our findings stress the value of combining banding cytogenetics with FISH and molecular techniques to better assess rearrangements in leukemia.

Introduction

The t(4;11)(q21;q23) occurs in 3%–6% of adult acute lymphoblastic leukemia (ALL) and is associated with a poor prognosis [1], [2]. It results in the fusion of the MLL gene located in 11q23 to the AF4 gene on 4q21 and generates a 5′MLL-3′AF4 fusion gene on the derivative chromosome 11. The chimeric transcript of this fusion gene can be detected by reverse transcriptase polymerase chain reaction (RT-PCR) [3], [4].

A few patients with the 5′MLL-3′AF4 rearrangement lacking or associated with a variant or complex t(4;11) have now been described [5], [6], [7], [8]. We report here the insertion of material of a chromosome 11 into a chromosome 4 resulting in the location of the 5′MLL-3′AF4 fusion gene on the derivative chromosome 4.

Section snippets

Case report

A 69-year-old woman was first seen for treatment of ALL associated with a severe diffuse intravascular coagulopathy. Neither adenopathies nor hepatosplenomegaly were noted during the physical examination upon admission. Hematologic data were as follows: hemoglobin 11.4 g/dL; and white blood cell (WBC) counts 75.8×109/L with 77.5% blast cells, 12.5 lymphocytes, 5% neutrophils, 2% monocytes, and platelets 46×109/L.

The bone marrow aspirate showed hypercellularity, with 90% lymphoblasts having a

Conventional cytogenetics

Cytogenetic analysis with R-banding of the patient's bone marrow cells was performed at the time of diagnosis and at the time of complete hematologic remission, as previously described [9].

Molecular cytogenetics

Dual-color fluorescence in situ hybridization (FISH) was performed using whole chromosome painting (WCP) probes specific to chromosome 4 (WCP4 labeled with SpectrumRed; Qbiogene, Illkirch, France) and chromosome 11 (WCP11 labeled with digoxygenin; Qbiogene), as previously described [9]. Direct

Results

Cytogenetic studies with R banding showed a 46,XX,ins(4;11)(q21;q13q23)[3]/46,idem,−22,+mar[18] karyotype in the bone marrow culture (Fig. 1).

FISH analysis with wcp4 and wcp11 confirmed the insertion of part of a chromosome 11 in the long arm of a chromosome 4 (Fig. 2). Using MLL dual-color probes, the portion centromeric of the MLL gene bcr (SpectrumGreen) was found on the der(4) whereas the portion telomeric of bcr (SpectrumOrange) was on the der(11) (Fig. 3). Thus, the derivative chromosomes

Discussion

The patient reported here had several features, including high white blood cell and blast counts with a pre-B phenotype (CD19+, CD10), which are usually observed in patients carrying the t(4;11) [8].

A review of the literature identified two cases, which were reported before the MLL-AF4 fusion gene was recognized, involving an insertion between chromosomes 4 and 11. In the first case, band q23 of a chromosome 11 was inserted in band q21 of a chromosome 4 [12] and in the second, it was part of

Acknowledgements

The authors thank Nadia Guéganic, Marie-Françoise Scoazec, Nicole Pichavant, and Pierre Roudaut for their skillful technical assistance.

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    In contrast to the classic t(9;11)(p21;q23) (the principal cause of a MLL-MLLT3 fusion; Fig. 3A3), no reciprocal gene fusion could be detected in the insertion cases. MLL insertions implicated various chromosome arms, such as Xq [9–16], 1q [17,18], 2q [19], 3p [20], 4q [17,21–24], 5q [25–27], 6q [17,28,29], 9q [30], and 10p [31–42] (Table 1). The insertions involving MLL result in most of the reported cases in fusion genes, but insertions of MLL without evidence of MLL gene fusion were also reported [43–45].

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