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A 78-year-old man was hospitalized because of rapid progression of chronic renal failure and diagnosed with multiple myeloma (MM) IgG-λ type ISS-III R-ISS-II with complex karyotype including t(14;19). Even after receiving bortezomib-based regimens, his renal failure progressed. He became dependent on dialysis, which was required three times a week. After introducing the daratumumab (DARA)-based regimen, his renal function improved, the frequency of dialysis decreased to twice a week, and the free light chain (FLC) ratio also improved. However, his myeloma eventually followed a refractory course; therefore, pomalidomide (POM)-dexamethasone (Pd) regimen was administered. Pd regimen had a marked effect and normalized the FLC ratio after three courses of the treatment. However, his myeloma reprogressed with multiple extramedullary masses and he became del(17p) positive; eventually, he died on the 470th day of disease. MM with t(14;19) is rare and has a poor prognosis with a highly aggressive course; however, early introduction of DARA or POM may provide long-term response.

We present a pediatric case of acute lymphoblastic leukemia (ALL) with chromosomal translocation 1;19 lacking E2A-PBX1 chimeric transcripts. On admission, the patient showed remarkable splenomegaly. Laboratory findings demonstrated that WBC was 12900/microl with blasts 61.5%. Bone marrow examination revealed 1282 X 10(3)/microl of the nucleated cell count with 95.5% lymphoblasts. Surface marker analysis showed an early pre-B lineage immunophenotype (CD10+, CD19+, CD34+, surface Ig-). Although G-banding chromosomal analysis showed 46,XY,der(19)t(1;19)(q23;p13), E2A-PBX1 chimeric transcripts and E2A gene rearrangement were not detected with the polymerase chain reaction method and Southern blot analysis, respectively. The patient was assigned to high-risk ALL according to the criteria of the Japan Association of Childhood Leukemia Study. His clinical response to prednisolone monotherapy for the initial 7 days and subsequent multidrug chemotherapy was excellent, and he achieved complete remission on day 15, which has lasted for more than 30 months. We reviewed the bibliography of the clinical and biological features of 17 children with t(1;19)+E2A-PBX1- ALL including this case. The two prominent characteristics included an early pre-B immunophenotype (11/13) and hyperdiploid (>50 chromosomes) chromosome abnormality (8/14). However, there was substantial heterogeneity in the demographic features and prognosis. Further accumulation of such patients will facilitate the determination of the appropriate treatment for childhood t(1;19)+E2A-PBX1- ALL.

We reported a 73-year-old woman of spinocerebellar ataxia 6 (SCA 6). There was no family history of neurological diseases. She demonstrated cerebellar ataxia and scanning speech at the age of 48. These symptoms gradually developed. Brain MRI showed severe cerebellar atrophy and no abnormality in the brain stem. Her neurological symptoms and MRI findings were compatible with cerebellocortical atrophy (CCA). Analysis of the CACNL1A4 gene on chromosome 19p 13 demonstrated she had an expanded allele with 27 CAG repeats. Therefore, she was diagnosed with SCA 6. In spite of her large CAG expansion, there was no family history of SCA 6 in this case. SCA 6 needs to be ruled out in cases of clinical CCA.

The mutation underlying myotonic dystrophy is the expansion of polymorphic CTG repeat in the 3'-noncoding region of the myotonin protein kinase (MtPK) gene mapping to chromosome 19q13.3. A full-length cDNA of human MtPK was cloned and expressed in COS-1 cells. We purified native full-length MtPK from rat skeletal muscle. This 70 kDa MtPK is localized in sarcoplasmic reticulum fraction, whereas the previously reported 55 kDa protein was observed in nuclear extract or the sarcoplasmic reticulum membrane. Based on the cDNA sequence, human MtPK was previously reported to have two amino acid sequence variations at the C-terminus, one GAARAP (RAP type) and PALPEP (PEP type). The MtPK purified appeared to be almost entirely RAP type. Stable expression of MtPK in mouse C2C12 cells caused the activation of chloride efflux. Expansion of CTG repeats suppressed myogenic differentiation. Collectively, the results indicate that prolonged MtPK activation provides a link between intracellular signal transduction pathway and membrane permeability.

The mutation underlying myotonic dystrophy is the expansion of polymorphic CTG repeat in the 3'-noncoding region of the myotonin protein kinase (MtPK) gene mapping to chromosome 19q13.3. A full-length cDNA of human MtPK was cloned and expressed in COS-1 cells. MtPK is recovered from the COS cell extract as a 70 kDa protein, which coincides with the size deduced from the predicted amino acid sequence. Biochemical characteristics of MtPK expressed in COS cells and its expression are investigated.

E2A gene rearrangements and E2A-PBX1 chimeric mRNA produced by t(1;19) were examined in 50 cases with acute lymphoblastic leukemia (ALL). Nine of 10 ALL cases with t(1;19) showed the rearrangement by Southern blotting using the E2A gene probe when digested with Xba I, Bgl II, and Eco RI, and the remaining one having hyperdiploidy which was considered to be a sign of good prognosis, lacked E2A rearrangement. Six of 7 ALL cases with t(1;19) that were tested showed the predicted 164 bps band of E2A-PBX1 chimeric mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), while a case having t(1;19) without E2A rearrangement and 10 cases lacking t(1;19) did not. Three ALL cases tested did not have E2A-PBX1 mRNA at the time complete remission 4 months after diagnosis. Forty ALL cases lacking t(1;19), including 4 cases with t(11;19), did not reveal rearrangement of E2A. We conclude that t(1;19)-ALL can be molecularly diagnosed, and minimal residual disease could be detected by the RT-PCR method.

Myotonic dystrophy (DM) is the most common muscular dystrophy affecting adults among Caucasian and Japanese populations, with an average incidence of 12.5 in 100,000 in Caucasians and 5.5 in 100,000 in the Japanese. Recently the DM gene was cloned and characterized showing homology with the family of serine-threonine protein kinase. In DM patients expansion of an unstable trinucleotide CTG repeat, located within the 3' untranslated region of DM kinase gene, is involved. In this review we outline the molecular biological aspects of DM including DNA diagnosis, anticipation, differences between paternal and maternal transmission, founder chromosome and expression of the gene.

The patient with quadruple cancer was a 32 year-old female who had osteosarcoma, bilateral breast cancer and adenocarcinoma of the lung. When chromosomal analysis of peripheral blood lymphocyte was performed, two abnormal cells were detected among 42 cells examined. The first cell showed a translocation involving chromosome 1 and 20 and trisomic for chromosome 19. The second cell was trisomic for chromosome x. Southern blot analysis of DNA from peripheral blood lymphocyte revealed that there was no difference in the expression of Rb gene between the patient and healthy adult.

The t(1;19)(q23;p13) seen in approximately 5% of childhood acute lymphoblastic leukemia (ALL) has been reported to be associated with leukoencephalopathy. 1;19 translocation can alter the E2A gene, leading to formation of a chimeric E2A-PBX1 gene that retain the activator domain of the E2A gene but substitute a homeobox domain of the PBX1 gene for the helix-loop-helix DNA binding and dimerization domain of E2A. The translocation breakpoints occurs within a single intron of the E2A gene on chromosome 19, and interrupts a homeobox gene, PBX1, on chromosome 1q23. Most cases with t(1;19) have been identified to have rearranged band of E2A by Southern blotting analysis, and to contain identical E2A-PBX1 chimeric transcripts by use of polymerase chain reaction assay. The molecular breakpoints in pre-B cases differ from those in early pre-B cases among t(1;19)-ALL. Thus, molecular analysis is useful for detection of t(1;19)-ALL.

The 14;19 translocation [t(14;19) (q32;q13)] is a recurring chromosomal translocation observed in leukemic cells of chronic lymphocytic leukemia showing prolymphocytic transformation. We have cloned the breakpoint junction of the translocation and identified a new gene, bcl-3, on the chromosome band 19q13 adjacent to the breakpoint. The translocation occurred at the switch region of the alpha constant locus of the immunoglobulin heavy chain gene and the upper stream of the bcl-3 gene, resulting in a head-to-head recombination between the two genes on the 14q+ chromosome. The bcl-3 gene was highly expressed in the leukemic cells carrying the 14;19 translocation. The bcl-3 gene product contained repeat structures found in proteins involved in cell cycle control and cell lineage determination. These results suggest that the bcl-3 is a proto-oncogene that may contribute to the development of leukemias carrying the 14;19 translocation.

For the purpose of cloning the gene of myotonic dystrophy (DM) using the technique of reverse genetics, we have introduced new methods such as microdissection, a YAC library and a Not I linking library and cloned many DNA fragments derived from the region of 19q13.2. Then we have assigned these to chromosome 19 by linkage map (CEPH families and linkage disequilibrium) and physical map (PFGE and in situ hybridization). Here we have described these methods.

We studied the clinical and cytogenetic features of 14 acute lymphoblastic leukemia (ALL) patients with 1; 19 translocation. Ten patients had poor prognostic factors such as age over 10 years, hyperleukocytosis over 5 X 10(4)/microliters or high serum lactic dehydrogenase levels over 5,000 IU/l. Two patients had relapsed within 12 months after the onset, but their 5-year survival rate was 84.6%. Cytogenetically, 6 of 14 patients had multiple subclones. Two had the clones with hyperdiploidy greater than 50 chromosomes, which was known to be one of the favorable prognostic factors in childhood ALL. These findings show ALL children with 1; 19 translocation have a more favorable outcome in spite of some high-risk features than hitherto been thought.

We have experienced and treated seven patients of pre-B cell leukemia in childhood. Clinical, cytological and ultrastructural characteristics of them were studied. Most of them had higher counts of white blood cells, hepatosplenomegaly, high value of lactic dehydrogenase and various karyotype abnormalities at onset. The chromosomal translocation t (1; 19) that is supposed to be specific to pre-B cell ALL was found in four of seven of our cases. In the seven patients, survival was studied in comparison to that of 27 common ALL patients at our hospital that are common in childhood acute leukemia. Although no difference in remission duration and survival time between pre-B cell ALL patients and common ALL group, there have been seen the tendency that remission and survival were of shorter duration for patients with pre-B cell ALL.

Four balanced autosomal reciprocal translocations were found through mitotic chromosome analysis among 72 subfertile males, 27 with azoospermia and 45 with sperm counts below 40 X 10(6)/ml. They were 46, XY, t(3; 20; 21) with azoospermia, 46, XY, t(14; 21) with sperm counts below 1 X 10(6)/ml, 46, XY, t(1; 19) lqh+ with azoospermia and 46, XY, t(3; 16) with sperm counts 27 X 10(6)/ml. Histological, cytogenetic and hormonal analysis were performed. Testicular biopsies from the first 3 carriers revealed complete spermatogenic arrest at the spermatocyte stage and meiotic studies of the same biopsies showed severe reduction in numbers of cells in 2nd meiotic division. In spite of severely defective spermatogenesis, serum gonadotropins of the carriers were within normal range, except for LH of the 4th case. Other chromosomal aberrations observed were 5 Klinefelter's syndrome, 2 autosomal minor variants (46, XY, 15p+ and 46, XY, 14s+) and 1 small Y.