Keiko Hashimoto

Correlations of chromosome abnormalities with histologic and immunologic characteristics in 49 patients from Akita, Japan with non-Hodgkin lymphoma.

We have analyzed the chromosomes of 49 non-Hodgkin lymphoma patients from an area of Japan that is nonendemic for adult T-cell leukemia/lymphoma. Clonal chromosome abnormalities were found in the majority (88%) of the specimens examined. The most characteristic structural abnormalities were: t(14;18)(q32;q21), t(3;22)(q27;q11), t(11;14)(q13;32), idic(18)(p11.2), and the combination del(1)(p13) and del(1)(q11). The t(14;18) were found in four of five follicular lymphomas and in one diffuse lymphoma. The breaks at 3q27 included seven translocations and an inv(3)(q12q27). A t(3;22) was found in three patients, all B-cell type, two of whom had kappa phenotype and one of whom was negative for the surface Ig. Fifteen of 49 cases had deletion of 6q. The common deleted region was found only in the segment distal to 6q21. These findings indicate the high percentage of t(14;18) in follicular lymphomas, which is unusual in Japan, and the high incidence of 3q27 translocations.

Duplication of chromosome 9 carrying a BCR/ABL chimeric gene in Philadelphia chromosome negative chronic myeloid leukemia

We investigated a patient with Philadelphia chromosome (Ph) negative but BCR positive chronic myeloid leukemia (CML) by fluorescence in situ hybridization (FISH). In the chronic phase one chromosome 9 contained a BCR/ABL fusion gene instead of chromosome 22. Although in blast crisis, both chromosomes 9 had BCR/ABL fusion genes. This could be caused by duplication of the rearranged chromosome 9, which may have a significance similar to a double Ph chromosome. This may suggest that the critical event in CML is the formation of a BCR/ABL chimeric gene regardless of its locus in the genome.

A New Variant Translocation of t(15;17) in a Patient with Acute Promyelocytic Leukemia (M3): t(15;19;17)(q22;p13;q12)

The reciprocal translocation (15;17) is specifically associated with acute promyelocytic leukemia [APL; M3 subtype according to French-American-British (FAB) classification]. A few patients with this disease have complex variant translocations. We describe a patient with M3 carrying t(15;19;17)(q22;p13;q12), which is a new type of variant translocation. The karyotypic interpretation was confirmed by Southern blot analysis with the use of RAR alpha and by fluorescence in situ hybridization (FISH) with the use of painting probes of chromosomes 15, 17, and 19 and a (15;17) translocation DNA probe. The results support the idea that the key event in APL is the formation of fusion gene PML/RAR alpha on the der(15).

Translocation (8;17)(p21;q21), a possible variant of t(15;17), in acute promyelocytic leukemia.

We report a 64-year old man with typical features of acute promyelocytic leukemia (APL) [M3, French-American-British (FAB) classification] in whom a variant, t(8;17)(p21;q21), was detected. This is the second case of the same variant translocation to be reported. The breakpoint on 17q was similar to those described in cases with a standard translocation 15;17. Consequently, this chromosome break or rearrangement at band 17q21, rather than the recipient site of translocation of the deleted material, appears to be of crucial importance in the genesis of APL.

Translocation (8;12;21)(q22.1;q24.1;q22.1): A New Masked Type of t(8;21)(q22;q22) in a Patient with Acute Myeloid Leukemia

The translocation t(8;21)(q22;q22) is found in 40% of cases of acute myeloid leukemia (AML) designated as the subtype M2 in the French-American-British (FAB) classification. The 8;21 translocation is clinically of interest because patients with this subtype have a good prognosis. We describe a masked type of the translocation, t(8;12;21)(q22.1;q24.1;q22.1). The translocation was first interpreted as t(8;12)(q22;q24) based on cytogenetics, but was reevaluated as a result of Southern blot and fluorescence in situ hybridization (FISH) analyses.

11q23 Aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone

We report on 2 patients with acute leukemia who had an 11q23 chromosomal aberration as an additional change after treatment with etoposide and mitoxantrone, agents that affect topoisomerase II (Topo II). One patient with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (L2) received chemotherapy, including 1,000 mg of etoposide and 75 mg of mitoxantrone. She relapsed 10 months later. Analysis at time of relapse showed a chromosomal aberration of del(11)(q23) as an additional cytogenetic change. The other patient was diagnosed with acute monoblastic leukemia (M5a) and received two autologous peripheral blood stem‐cell transplantations. Her cumulative doses of etoposide and mitoxantrone were 6,000 mg and 42 mg, respectively. She also relapsed, and analysis at that time revealed del(11)(q23) as an additional chromosomal aberration. The mixed lineage leukemia/(myeloid‐lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy‐related leukemias caused by Topo II Inhibitors. Based on these two cases, it may be that Topo II inhibitors can cause clonal evolution affecting chromosome band 11q23.

REARRANGEMENTS OF THE BCL6 GENE AND CHROMOSOME ABERRATIONS AFFECTING 3Q27 IN 54 PATIENTS WITH NON-HODGKIN'S LYMPHOMA

Chromosome aberrations affecting 3q27 are among the most frequent non-random abnormalities in non-Hodgkins lymphomas (NHL), especially the diffuse, large cell type. Recently, an association between BCL6 rearrangement and frequent extranodal lesions, rare bone marrow infiltration and a favorable clinical outcome was reported. We performed molecular studies of the BCL6 gene in 54 patients with NHL. Twelve patients (22%) with rearranged BCL6 genes were selected for histological, clinical, molecular, and cytogenetic studies. Ten of these cases were diffuse, large cell type lymphoma, one a follicular lymphoma, and one a mantle cell lymphoma (MCL). All cases were of the B-cell type and this is the first time a rearranged BCL6 gene has been found in an MCL. Cytogenetic data for 10 cases were available and the partner sites of the 3q27 translocation were determined in 7 of 10 patients. These locations were variable, including 6p21.3, 9p22, and 14q11 in addition to the immunoglobulin loci 14q32 (IGH), 2p12 (IGK), and 22q11 (IGL). The heterogeneity in partner sites is distinct from other lymphoma subgroups and may suggest that the genetic events are not uniform among patients with BCL6 rearrangements.

Ph+ Acute Myelogenous Leukemia with t(7;11)(p15;p15) and Clonal Evolution in Relapse after Bone Marrow Transplantation

A 20-year-old female with Ph+ acute myelogenous leukemia (M2) associated with t(7;11)(p15;p15) is reported. Bone marrow aspirates were hypercellular with leukemic cells including Auer rods. Chromosome analysis showed t(7;11) and the Ph chromosome. After complete remission, normal karyotype was restored. Normal male karyotypic cells replaced the bone marrow following allogeneic bone marrow transplantation from her brother. On day 358, cytogenetic study at relapse revealed 14q+ as an additional change and clearly showed that the abnormal clone was derived from the patient, because metaphases with XX were all of abnormal karyotype and those with XY were normal.

Acute Interstitial Nephritis with Symmetric Enlargement of the Lacrymal and Salivary Glands and Systemic Lymphadenopathy

We describe a 40-year-old man who developed symmetric enlargement of the lacrymal and salivary glands and systemic lymphadenopathy. Laboratory findings included eosinophilia, polyclonal hypergammaglobulinemia, elevated circulating immune complexes, hypocomplementemia, and renal insufficiency. The lymph node pathology was atypical of angioimmunoblastic lymphadenopathy with disproteinemia (AILD), in that it lacked a prominence of arborizing small vessel proliferation. Despite extensive examinations, the cause of the atypical AILD process has not been identified. However, a flow-cytometric analysis of immunophenotypes of lymphoid cells from the lymph node revealed a predominance of activated helper/inducer T cells, indicating a hyperimmune state. Acute interstitial nephritis was secondary to the renal propagation of the atypical AILD process. Thus, atypical AILD can be a new cause of acute interstitial nephritis. A course of combined steroids and immunosuppressive treatment resolved those pathologic disorders for 5 years.

Translocation (9;11;22)(p22;q23;q11): A new type of complex variant translocation of t(9;11)(p22;q23) with MLL rearrangement

We describe a patient with acute monocytic leukemia (M5a, FAB classification) associated with a new type of variant translocation (9;11). Southern blot analysis showed the rearrangement of the MLL (ALL-1/HRX) gene at 11q23. Fluorescence in situ hybridization (FISH) with painting probes of chromosomes 9, 11, and 22 revealed the translocation as t(9;11;22) (p22;q23;q11). This is more evidence that the production of chimeric mRNA following the translocation of the LTG9 (MLLT3/AF9) gene at 9p22 to 11q is a critical event in this leukemia subtype.