Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki.

Identification of cytogenetic abnormalities is an important clue for the elucidation of carcinogenesis. However, the cytogenetic and clinical significance of adult T-cell leukemia/lymphoma (ATLL) is still unclear. To address this point, cytogenetic findings in 50 cases of ATLL were correlated with clinical characteristics. Karyotypes showed a high degree of diversity and complexity. Aneuploidy and multiple breaks (at least 6) were observed frequently in acute and lymphoma subtypes of ATLL. Breakpoints tended to cluster at specific chromosomal regions, although characteristic cytogenetic subgroups of abnormalities were not found. Of these, aberrations of chromosomes 1p, 1q, 1q10-21, 10p, 10p13, 12q, 14q, and 14q32 correlated with one or more of the following clinical features: hepatosplenomegaly, elevated lactate dehydrogenase, hypercalcemia, and unusual immunophenotype, all indicators of clinical severity of ATLL. Multiple breaks (at least 6); abnormalities of chromosomes 1p, 1p22, 1q, 1q10-21, 2q, 3q, 3q10-12, 3q21, 14q, 14q32, and 17q; and partial loss of chromosomes 2q, 9p, 14p, 14q, and 17q regions correlated with shorter survival. These cytogenetic findings are relevant in predicting clinical outcome and provide useful information to identify chromosomal regions responsible for leukemogenesis. This study also indicates that one model of an oncogenic mechanism, activation of a proto-oncogene by translocation of a T-cell-receptor gene, may not be applicable to the main pathway of development of ATLL and that a multistep process of leukemogenesis is required for the development of ATLL. (Blood. 2001;97:3612-3620)

Identification of an aberrant type of rearrangement in the T-cell receptor alpha/delta locus in adult T-cell leukemia.

V(D)J recombination is the mechanism by which antigen receptor genes are assembled by three basic steps: cleavage, processing of broken DNA ends, and joining. In this process of recombination, the broken DNA molecules excised from different receptor gene loci are often joined to generate interlocus joints. The interlocus recombination process contributes to the translocation between antigen receptor genes and oncogenes, leading to the malignant transformation of lymphocytes. The alpha and delta chain of the T-cell receptor (TCR alpha/delta) locus at chromosome 14q11 is also a region where several types of chromosome translocations occur in T-cell malignancies. In the process of analyzing TCR alpha rearrangements in a patient with adult T-cell leukemia (ATL) carrying a translocation at chromosome 14q11, we found novel complex rearrangements in the Jalpha locus. On the one hand, the V2.3 gene is joined to the heptamernonamer recombination signal sequence of the J37 gene, and, on the other hand, the J37 gene is joined to the V2.3 recombination signal sequence through head-to-head fusion. These recombination products or hybrid joints originated through an inversion of about 70kb DNA. Interestingly, the inverted DNA stretch contains a normal V8.1-J40 rearrangement. These findings are the first direct demonstration that successive rearrangements with hybrid joints occur on the same chromosome in the human TCR alpha locus.

[Chromosome 1 abnormalities at band 1p32 in two atomic bomb survivors with myelodysplastic syndrome].

We reported on 2 atomic bomb survivors(a 60-year-old man and 63-year-old woman)suffering myelodysplastic syndrome(MDS) associated with 1p32 chromosomal abnormalities. They were exposed to atomic bomb radiation at distances of 1.2 and 1.1 km, respectively, and were given a diagnosis of MDS 44 and 46 years after the bombing, respectively. The male patient had refractory anemia(RA) and a bone marrow cell karyotype of 46, XY, del(1)(p22p32), t(8;11)(p11;p15). The female patient had RA with excess of blasts (RAEB) and a karyotype of 45, X, -X, t(1;11)(p32;q23), +del(1)(p32), inv(3) (p21q27), del(5)(q15), -6, -9, -19, +mar 1, +mar 2. Multi-separated nuclear megakaryocytes were observed in both patients. These findings suggested that they had been exposed to radiation near the atomic explosion despite the fact that their symptoms of MDS developed more than 40 years after the bombing. 1p32 is known to be the locus of the TAL1 gene. However, Southern blot analysis did not reveal rearrangement of the TAL1 gene in the male patient.

Consistent detection of CALM-AF10 chimaeric transcripts in haematological malignancies with t(10;11)(p13;q14) and identification of novel transcripts.

The t(10;11)(p13-14;q14-21) is a rare but recurring translocation associated with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Recently the CALM gene was cloned from the t(10;11) breakpoint of U937 and fused to AF10, a putative transcription factor, which had been identified as one of the fusion partners of the MLL gene. In order to define the involvement of these genes in primary leukaemias and cell lines with t(10;11), we analysed the expression of fusion transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR) in five patient samples including ALL, AML and lymphoblastic lymphoma, and three monocytic cell lines (P31/Fujioka, KP-Mo-TS and U937). The CALM-AF10 fusion transcript was detected in all samples; however, the AF10-CALM fusion was not detected in two patient samples and one cell line. In RT-PCR analysis there were six isoforms of the CALM-AF10 fusion transcripts and five of AF10-CALM fusion transcripts. We also detected novel transcripts in U937. Sequence analysis revealed that all these isoforms had in-frame junctions and that some of them resulted from alternative splicing at different exons of CALM and others from different breakpoints at CALM and/or AF10. There were at least two different breakpoints of CALM and three of AF10 gene. Our results suggest that the CALM-AF10 fusion gene is a constant feature and is involved in the pathogenesis of haematological malignancies with t(10;11)(p13-14;q14-21), showing various and often multilineage phenotypes. Thus, t(10;11) needs to be investigated by RT-PCR for identification of the genes involved.

[Intracranial and orbital extension of a nasal cavity adult T-cell leukemia: a case report].

Adult T-cell leukemia (ATL) is one kind of leukemia induced by human T lymphotropic virus type I (HTLV-I) infection. An unusual case of ATL is presented. A fifty-one-year-old male patient was admitted to our hospital because of nasal obstruction and blindness in the left eye. Imaging study revealed a mass lesion in the nasal cavity, the left paranasal sinus extending to the left orbit and intracranial frontal base. Biopsy of the mass from the paranasal sinus was carried out and the histological diagnosis was a granulomatous lesion with non-specific inflammation. The clinical impression of the lesion was lethal midline granuloma. After steroid therapy and 50 Gy of local radiotherapy, the patient's symptoms disappeared except for his blindness in the left eye. Imaging study revealed that the mass lesion had become smaller. In spite of local improvement, new lesions such as cervical lymph node swelling and multiple nodular shadows in the lung fields appeared on CT scan. Histological diagnosis of the biopsied cervical lymph node was T-cell dominant non-Hodgkin's lymphoma of the diffuse type. Serologically, anti-HTLV-I antibody was positive. Southern blot analysis of lymph node biopsy showed monoclonal proliferation of ATL cells. We made the diagnosis of our case as ATL. The patient died 16 months later despite repeated systemic chemotherapy with cyclophosphamide, vincristine, adriamycin, and prednisolone. ATL can involve the central nervous system (CNS) and manifest CNS symptoms. The neurosurgeon also should consider the CNS involvement of ATL especially in Japan.

High rate of chromosomal abnormalities in HTLV-I-infected T-cell colonies derived from prodromal phase of adult T-cell leukemia: a study of IL-2-stimulated colony formation in methylcellulose.

To detect chromosomal abnormalities in prodromal phase of adult T-cell leukemia (ATL), we established a clonal culture method for human T-lymphotropic virus type I (HTLV-I) infected T-cells in methylcellulose containing recombinant human interleukin 2 (rhIL-2). We tried to analyze chromosomes of 187 colonies (4, 23, 69, 74, and 17, from HTLV-I-uninfected normal T-cells, HTLV-I-Infected normal T-cells, HTLV-I carriers, smoldering ATL, and chronic ATL, respectively), using chromosomal banding methods. In the prodromal group, 53% of colonies (84/160) (36/69, 37/74, 11/17 in HTLV-I carriers, smoldering ATLs, and chronic ATL, respectively) had chromosomal abnormal clones. In HTLV-I carriers, multiple clones with simple chromosomal abnormalities were observed. In more progressed chronic ATL, more complex chromosomal abnormalities were detected, and specific colonies were selected. Thus, colonies in the prodromal phase of ATL are characterized by cytogenetical clonal evolution and clonal changes.

No parental origin bias for the rearranged chromosomes in myeloid leukemias associated with t(9;22), t(8;21) and t(15;17).

We investigated parental origin of rearranged chromosomes 9 and 22 (9q + and 22q -) in five patients with Ph-positive chronic myeloid leukemia (CML) using the C-banding and silver-staining methods of nucleolus organizer regions, respectively; of rearranged chromosome 21 (21q +) in seven patients with t(8;21)-positive acute myeloid leukemia (AML); and of rearranged chromosome 15 (15q +) in six patients with t(15;17)-positive AML. It was found that these rearranged chromosomes can be of either paternal or maternal origin. Although the number of patients examined was small, these results indicate that the genes rearranged as a result of these chromosome translocations (ABL, BCR, AML-1 and PML) are not genomically imprinted.

Successful treatment with cyclosporine in a case of hemophagocytic syndrome manifesting as severe liver dysfunction.

Forms of hemophagocytic syndrome, which affects mainly children, vary from mild to very severe and often fatal. We describe an adult patient with hemophagocytic syndrome in whom severe liver dysfunction developed. The condition continued to deteriorate despite treatment with plasma exchange, high-dose gamma globulin, and corticosteroid therapy. Treatment with cyclosporine (2.3 mg/kg/day) dramatically improved the condition and normalized liver function. Cyclosporine reduced the serum levels of ferritin, interferon-tau, interleukin-6, and soluble interleukin-2 receptor. These findings suggest that hemophagocytic syndrome accompanied with severe liver dysfunction results from hypercytokinemia, and cyclosporine is useful in preventing a fatal outcome during the acute phase.