24 results on '"Jhanwar, S."'
Search Results
2. Incidence of involvement of the B and T lymphocyte lineages in chronic myelogenous leukemia
- Author
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Nitta, M, Kato, Y, Strife, A, Wachter, M, Fried, J, Perez, A, Jhanwar, S, Duigou- Osterndorf, R, Chaganti, RS, and Clarkson, B
- Abstract
Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin- coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1- positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1- positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.
- Published
- 1985
- Full Text
- View/download PDF
3. t(3;22)(q27;q11): a novel translocation associated with diffuse non- Hodgkin's lymphoma [see comments]
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Offit, K, Jhanwar, S, Ebrahim, SA, Filippa, D, Clarkson, BD, and Chaganti, RS
- Abstract
Of 187 specimens of non-Hodgkin's lymphoma and four hyperplastic lymphoid proliferations with clonal chromosome abnormalities ascertained serially over a 4 1/2-year period, nine cases with t(3;22)(q27;q11) were identified. Seven of the lymphomas were diffuse tumors, predominantly large cell type. The eighth tumor, a follicular small cleaved cell lymphoma, exhibited a t(3;22) and a t(14;18)(q32;q21). The ninth case was a lymph node from a human immunodeficiency virus-positive patient which showed atypical hyperplasia. Overall survival of t(3;22) diffuse lymphoma patients was not different from that of patients with abnormal karyotypes without t(3;22). The t(3;22) diffuse tumors studied showed a disproportionate frequency of lambda light chain on their cell surfaces, a finding similar to that observed in t(8;22)(q24;q11) Burkitt's lymphomas. Our results indicate that the t(3;22)(q27;q11) is the third most common recurring translocation in diffuse non-Hodgkin's lymphoma.
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- 1989
- Full Text
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4. Growth characteristics of leukemic and normal hematopoietic cells in Ph' + chronic myelogenous leukemia and effects of intensive treatment
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Goto, T, Nishikori, M, Arlin, Z, Gee, T, Kempin, S, Burchenal, J, Strife, A, Wisniewski, D, Lambek, C, Little, C, Jhanwar, S, Chaganti, R, and Clarkson, B
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- 1982
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5. Primary therapy of acute promyelocytic leukemia: results of amsacrine- and daunorubicin-based therapy
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Arlin, Z, primary, Kempin, S, additional, Mertelsmann, R, additional, Gee, T, additional, Higgins, C, additional, Jhanwar, S, additional, Chaganti, RS, additional, and Clarkson, B, additional
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- 1984
- Full Text
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6. CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy.
- Author
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Zhou P, Comenzo RL, Olshen AB, Bonvini E, Koenig S, Maslak PG, Fleisher M, Hoffman J, Jhanwar S, Young JW, Nimer SD, and Boruchov AM
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- Adult, Aged, Aged, 80 and over, Amyloidosis drug therapy, Amyloidosis immunology, Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Antigens, CD immunology, Female, Humans, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell immunology, Lymphoma, B-Cell metabolism, Male, Mice, Middle Aged, Plasma Cells immunology, Receptors, IgG immunology, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Syndecan-1 immunology, Syndecan-1 metabolism, Xenograft Model Antitumor Assays, Amyloidosis metabolism, Antigens, CD biosynthesis, Gene Expression Regulation immunology, Immunoglobulin Light Chains, Plasma Cells metabolism, Receptors, IgG biosynthesis
- Abstract
Despite advances in therapy, many patients with systemic light-chain amyloidosis (AL) die within 3 years from diagnosis. The humanized 2B6 monoclonal antibody (MoAb) is specific for the low-affinity IgG Fc receptor CD32B and effective in a human CD32B+ B-cell lymphoma murine xenograft model. Because MoAb therapy could improve outcomes in AL, we studied CD32B expression by clonal plasma cells obtained from 48 patients with AL. Transcript profiling showed that expression of CD32B was significantly higher than expression of all other Fc receptor family members. Reverse-transcriptase polymerase chain reaction (RT-PCR) using double-enriched CD138+ plasma cells showed uniform expression of the stable cell surface CD32B1 isoform at diagnosis and relapse, and flow cytometry showed intense CD32B cell surface staining on 99% of CD138+ plasma cells at diagnosis and relapse. These data provide a rationale for the novel therapeutic targeting of CD32B using the humanized 2B6 MoAb in patients with systemic AL-amyloidosis.
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- 2008
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7. Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element.
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Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, Jhanwar S, Moore MA, and Nimer SD
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- Animals, Antigens, CD34 analysis, Cell Culture Techniques methods, Cell Differentiation, Cell Division, Cells, Cultured transplantation, Colony-Forming Units Assay, Core Binding Factor Alpha 2 Subunit, Hematopoietic Stem Cells metabolism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins physiology, Reproducibility of Results, Signal Transduction, Telomerase analysis, Transduction, Genetic, Hematopoietic Stem Cells cytology, Oncogene Proteins, Fusion physiology, Transcription Factors physiology
- Abstract
Hematopoiesis is a complex process involving hematopoietic stem cell (HSC) self-renewal and lineage commitment decisions that must continue throughout life. Establishing a reproducible technique that allows for the long-term ex vivo expansion of human HSCs and maintains self-renewal and multipotential differentiation will allow us to better understand these processes, and we report the ability of the leukemia-associated AML1-ETO fusion protein to establish such a system. AML1-ETO-transduced human CD34+ hematopoietic cells routinely proliferate in liquid culture for more than 7 months, remain cytokine dependent for survival and proliferation, and demonstrate self-renewal of immature cells that retain both lymphoid and myeloid potential in vitro. These cells continue to express the CD34 cell surface marker and have ongoing telomerase activity with maintenance of telomere ends, however they do not cause leukemia in nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice. Identification of the signaling pathways that are modulated by AML1-ETO and lead to the self-renewal of immature human progenitor cells may assist in identifying compounds that can efficiently expand human stem and progenitor cells ex vivo.
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- 2003
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8. Chromosome 19 abnormalities are commonly seen in AML, M7.
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Nimer SD, MacGrogan D, Jhanwar S, and Alvarez S
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- Chromosome Aberrations, Chromosomes, Human, Pair 19, Humans, Trisomy, Leukemia, Megakaryoblastic, Acute genetics
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- 2002
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9. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets.
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Dyomin VG, Palanisamy N, Lloyd KO, Dyomina K, Jhanwar SC, Houldsworth J, and Chaganti RS
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- B-Lymphocyte Subsets pathology, Base Sequence, Chromosome Mapping, Gene Expression Regulation, Neoplastic, Gene Rearrangement, Genetic Markers, Humans, Lymphoma, B-Cell pathology, Molecular Sequence Data, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 14, Lymphoma, B-Cell genetics, Mucins genetics, Translocation, Genetic
- Abstract
The band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cgamma) probe. The translocation linked the IGHG4 switch (Sgamma4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably, MUC1 transcription is aberrantly regulated by the IGHA (Calpha) 3' enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3' MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis. (Blood. 2000;95:2666-2671)
- Published
- 2000
10. Multicolor spectral karyotyping identifies new recurring breakpoints and translocations in multiple myeloma.
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Rao PH, Cigudosa JC, Ning Y, Calasanz MJ, Iida S, Tagawa S, Michaeli J, Klein B, Dalla-Favera R, Jhanwar SC, Ried T, and Chaganti RS
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- Aged, Aged, 80 and over, Biopsy, Bone Marrow ultrastructure, Chromosome Banding, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 20, Female, Genetic Markers, Humans, Male, Middle Aged, Chromosome Breakage, Karyotyping methods, Multiple Myeloma genetics, Translocation, Genetic
- Abstract
Karyotypic information on multiple myeloma (MM) is less extensive than that on other myeloid or lymphoid malignancies due to low mitotic activity of plasma cells. An add(14)(q32) marker chromosome has been reported to be the most frequent recurring abnormality in clonally abnormal cases; in approximately one third of the latter cases, this marker has been identified as a der(14)t(11;14)(q13;q32) chromosome. To map chromosomal breakpoints, characterize the add(14)(q32) marker chromosomes, and to identify other recurring translocations in MM, we used spectral karyotyping (SKY) to analyze a panel of nine bone marrow (BM) biopsy samples from eight patients and 10 tumor cell lines derived from MM patients. SKY involves hybridization of 24 fluorescently labeled chromosome painting probes to metaphase spreads in such a manner that simultaneous visualization of each of the chromosomes in a different color is accomplished. By this method, it was possible to define all chromosomal rearrangements and identify all of the clonal marker chromosomes in tumor cells. By detailed mapping of breakpoints of rearrangement, it was also possible to identify several novel recurring sites of breakage that map to the chromosomal bands 3q27, 17q24-25, and 20q11. The partner chromosomes in translocations that generated the add (14)(q32) marker chromosomes were identified in all cases in which they were detected by G-banding (one biopsy and six cell lines). In addition, two new translocations involving band 14q32, ie, t(12;14)(q24;q32) and t(14;20)(q32;q11) have also been identified. These studies demonstrate the power of SKY in resolving the full spectrum of chromosome abnormalities in tumors., (Copyright 1998 by The American Society of Hematology.)
- Published
- 1998
11. Chromosomal and gene amplification in diffuse large B-cell lymphoma.
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Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L, Offit K, Jhanwar SC, and Chaganti RS
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- Chromosome Mapping, Humans, Translocation, Genetic, Chromosomes, Human, Gene Amplification, Lymphoma, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Chromosomal translocations leading to deregulation of specific oncogenes characterize approximately 50% of cases of diffuse large B-cell lymphomas (DLBL). To characterize additional genetic features that may be of value in delineating the clinical characteristics of DLBL, we studied a panel of 96 cases at diagnosis consecutively ascertained at the Memorial Sloan-Kettering Cancer Center (MSKCC) for incidence of gene amplification, a genetic abnormality previously shown to be associated with tumor progression and clinical outcome. A subset of 20 cases was subjected to comparative genomic hybridization (CGH) analysis, which identified nine sites of chromosomal amplification (1q21-23, 2p12-16, 8q24, 9q34, 12q12-14, 13q32, 16p12, 18q21-22, and 22q12). Candidate amplified genes mapped to these sites were selected for further analysis based on their known roles in lymphoid cell and lymphoma development, and/or history of amplification in tumors. Probes for six genes, which fulfilled these criteria, REL (2p12-16), MYC (8q24), BCL2 (18q21), GLI, CDK4, and MDM2 (12q13-14), were used in a quantitative Southern blotting analysis of the 96 DLBL DNAs. Each of these genes was amplified (four or more copies) with incidence ranging from 11% to 23%. This analysis is consistent with our previous finding that REL amplification is associated with extranodal presentation. In addition, BCL2 rearrangement and/or REL, MYC, BCL2, GLI, CDK4, and MDM2 amplification was associated with advanced stage disease. These data show, for the first time, that amplification of chromosomal regions and genes is a frequent phenomenon in DLBL and demonstrates their potential significance in lymphomagenesis.
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- 1998
12. Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization.
- Author
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Cigudosa JC, Rao PH, Calasanz MJ, Odero MD, Michaeli J, Jhanwar SC, and Chaganti RS
- Subjects
- Adult, Aged, Chromosome Banding, Female, Humans, Male, Middle Aged, Nucleic Acid Hybridization, Chromosome Aberrations, Chromosome Deletion, Genome, Human, Multiple Myeloma genetics
- Abstract
Clonal chromosomal changes in multiple myeloma (MM) and related disorders are not well defined, mainly due to the low in vivo and in vitro mitotic index of plasma cells. This difficulty can be overcome by using comparative genomic hybridization (CGH), a DNA-based technique that gives information about chromosomal copy number changes in tumors. We have performed CGH on 25 cases of MM, 4 cases of monoclonal gammopathy of uncertain significance, and 1 case of Waldenstrom's macroglobulinemia. G-banding analysis of the same group of patients demonstrated clonal chromosomal changes in only 13 (43%), whereas by CGH, the number of cases with clonal chromosomal gains and losses increased to 21 (70%). The most common recurrent changes detected by CGH were gain of chromosome 19 or 19p and complete or partial deletions of chromosome 13. +19, an anomaly that has so far not been detected as primary or recurrent change by G-banding analysis of these tumors, was noted in 2 cases as a unique change. Other recurrent changes included gains of 9q, 11q, 12q, 15q, 17q, and 22q and losses of 6q and 16q. We have been able to narrow the commonly deleted regions on 6q and 13q to bands 6q21 and 13q14-21. Gain of 11q and deletion of 13q, which have previously been associated with poor outcome, can thus be detected by CGH, allowing the use of this technique for prognostic evaluation of patients, without relying on the success of conventional cytogenetic analysis.
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- 1998
13. 6q deletions define distinct clinico-pathologic subsets of non-Hodgkin's lymphoma.
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Offit K, Parsa NZ, Gaidano G, Filippa DA, Louie D, Pan D, Jhanwar SC, Dalla-Favera R, and Chaganti RS
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- Biopsy, Chromosome Mapping, Humans, Karyotyping, Lymphoma, Non-Hodgkin pathology, Polymorphism, Restriction Fragment Length, Chromosomes, Human, Pair 6, Gene Deletion, Lymphoma, Non-Hodgkin classification, Lymphoma, Non-Hodgkin genetics
- Abstract
Commonly observed in lymphoid neoplasms, deletions of 6q have been correlated with histologic and clinical subsets of non-Hodgkin's lymphoma (NHL). Our recent analysis of loss of heterozygosity of 6q loci in NHL showed two regions of minimal molecular deletion (RMD), an RMD1 at 6q25-27 and an RMD2 at 6q21-23. To establish correlations between these RMDs and regions of minimal cytogenetic deletions (RCDs) on 6q, and to define associations between RCDs and clinico-pathologic features, we have analyzed chromosome 6 abnormalities in 459 consecutively ascertained, karyotypically abnormal cases of NHL. Among these, 126 (27.5%) cases had structural abnormalities of chromosome 6, of which 94 were deletions. Analysis of these deletions identified three RCDs. An RCD1 encompassing 6q25-27 was seen in 45 intermediate-grade NHL. An RCD2 at 6q21 was observed in 11 high-grade NHL, 9 of which were of the immunoblastic subtype. An RCD3 at 6q23 was noted in 18 low-grade NHL lacking a t(14;18) translocation. Of these 18 cases, 12 were small lymphocytic NHL and, in 2 of these, del(6q) was the sole karyotypic abnormality. In 20 cases of low-grade NHL with t(14;18), the deletions spanned both RCD1 and RCD3. These data suggested the presence of at least 3 tumor suppressor genes on 6q within RCD1, RCD2, and RCD3; they also showed associations between RCDs in 6q and subsets of NHL, including a specific association between a group of well-differentiated lymphoid neoplasms and RCD3. The apparent heterogeneity of breakpoints when all NHLs are considered together explains the inability of previous studies to reliably establish correlations between recurring 6q deletions and histologic and clinical features of NHL.
- Published
- 1993
14. t(9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's lymphoma with plasmacytoid differentiation.
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Offit K, Parsa NZ, Filippa D, Jhanwar SC, and Chaganti RS
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- Adult, Aged, Aged, 80 and over, Antigens, CD analysis, Antigens, CD19, Antigens, Differentiation analysis, Antigens, Differentiation, B-Lymphocyte analysis, B-Lymphocytes pathology, Cell Differentiation, DNA analysis, Female, Flow Cytometry, Humans, Immunoenzyme Techniques, Karyotyping, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Sialic Acid Binding Ig-like Lectin 2, Translocation, Genetic, Cell Adhesion Molecules, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 9, Lectins, Lymphoma, Non-Hodgkin genetics, Plasma Cells pathology
- Abstract
In this series of 426 consecutively ascertained, karyotypically abnormal non-Hodgkin's lymphomas (NHLs) derived from 407 patients, a t(9;14)(p13;q32) was encountered in 7 cases; an additional case demonstrated t(9;14)(p1?3;q32). At the time of detection of t(9;14), four cases were small lymphocytic lymphomas with plasmacytoid features; in three of these the t(9;14) was the sole karyotypic abnormality. In two cases of large-cell NHL demonstrating t(9;14), retrospective review of prior lymph node biopsies showed the presence of a small lymphocytic lymphoma of the plasmacytoid subtype. The remaining two cases comprised a large-cell lymphoma of the brain and a follicular NHL. Thus, six of eight cases (75%) had an initial identical low-grade histology. Immunohistochemical analysis of six cases showed no reactivity with CD1, CD2, CD4, CD5, CD8, and CD10 and high reactivity with CD19 and CD20. All four lymphocytic lymphomas and one of the two large-cell NHLs showed cytoplasmic Ig, consistent with plasmacytoid differentiation. Of the eight cases in this series, six presented with or developed stage IV disease; all were characterized by a 6-month to 5-year clinical phase of indolent disease before treatment was instituted. All five patients with low-grade NHL at the time of cytogenetic analysis were alive with recurrent disease at 3-year median follow-up. The remaining three patients with large-cell diffuse histologies relapsed after intensive therapy and expired at a median of 3 years from diagnosis; two of these showed previous or metachronous small lymphocytic tumors. These results suggest a novel biologically distinct subset of NHL; a neoplasm of mature B lymphocytes with plasmacytoid differentiation, characterized by t(9;14); and an indolent presentation followed by gradual clinical progression of disease.
- Published
- 1992
15. Clonal analysis of myelodysplastic syndrome: monosomy 7 is expressed in the myeloid lineage, but not in the lymphoid lineage as detected by fluorescent in situ hybridization.
- Author
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Gerritsen WR, Donohue J, Bauman J, Jhanwar SC, Kernan NA, Castro-Malaspina H, O'Reilly RJ, and Bourhis JH
- Subjects
- Adolescent, Aged, Antigens, Differentiation, B-Lymphocyte analysis, Antigens, Differentiation, Myelomonocytic analysis, Antigens, Differentiation, T-Lymphocyte analysis, B-Lymphocytes pathology, Bone Marrow pathology, Cell Separation, Child, Child, Preschool, Chromosome Disorders, Clone Cells, Female, Humans, Infant, Lymphocytes ultrastructure, Male, Myelodysplastic Syndromes pathology, Nucleic Acid Hybridization, T-Lymphocytes pathology, Chromosome Aberrations genetics, Chromosomes, Human, Pair 7, Monosomy, Myelodysplastic Syndromes genetics
- Abstract
Conflicting results have been published on whether or not myelodysplastic syndromes (MDS) affect all cell lineages. Involvement of myeloid and erythroid cell lineages has been regularly observed, but it remains controversial whether the different lymphoid cell lineages are involved. In this study of eight patients with MDS associated with monosomy 7, fluorescent in situ hybridization (FISH) was used to enumerate the chromosomes 7 in interphase cells. With the probe D7Z1, the rate of false-positive detection of monosomy 7 was 3% +/- 2% in normal cells. T- and B-cell lines were established from eight patients with MDS and monosomy 7. As determined by FISH in interphase cells, 1.9% (0% to 3%) of the cells in the B-cell lines showed one fluorescent spot and 1.1% (0% to 2.9%) of the cells in the T-cell lines. These values do not differ from normal values. However, the possibility that normal cells were selected when the T- and B-cell lines were established could not be excluded. Therefore, peripheral blood cells were obtained, separated according to surface markers specific for lymphoid and myeloid cell lineage with a cell sorter, and analyzed for the expression of monosomy 7 by FISH. Antibodies recognizing T cells (CD3), B cells (CD20), natural killer (NK) cells (CD57), monocytes and granulocytes (low and high expression of CD11b antigen), and myeloid progenitors (CD33) were used to separate cells. The expression of monosomy 7 in the T cells, NK cells, and B cells did not differ from control values. These results in the lymphoid subpopulations are in stark contrast with the observations in the myeloid populations; the percentage of cells with monosomy 7 ranged from 9% to 78% (controls: 6% +/- 2%) in cells with low CD11b expression, 20% to 89% in cells with a high expression of the CD11b antigen (controls: 7% +/- 3%), and 23% to 91% in the CD33 positive cells (controls: 5% +/- 3%). The results of this study suggest that monosomy 7 does not usually affect lymphoid subpopulations but is restricted to committed progenitor cells with the capacity to differentiate into mature myeloid cells.
- Published
- 1992
16. Follicular lymphoma with t(8;14)(q24;q32): a distinct clinical and molecular subset of t(8;14)-bearing lymphomas.
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Ladanyi M, Offit K, Parsa NZ, Condon MR, Chekka N, Murphy JP, Filippa DA, Jhanwar SC, Dalla-Favera R, and Chaganti RS
- Subjects
- Aged, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blotting, Southern, Chromosome Banding, DNA Probes, DNA, Neoplasm genetics, DNA, Neoplasm isolation & purification, Female, Genes, Immunoglobulin, Genes, myc, Humans, Immunoglobulin Heavy Chains genetics, Karyotyping, Lymphoma, Follicular classification, Lymphoma, Follicular drug therapy, Lymphoma, Follicular pathology, Male, Middle Aged, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 8, Lymphoma, Follicular genetics, Oncogenes, Translocation, Genetic
- Abstract
The presence of the translocation t(8;14)(q24;q32) has not been well described in follicular lymphoma (FL). In a consecutive series of 278 karyotypically abnormal non-Hodgkin's lymphomas (NHL), six patients with FL showing a t(8;14) without a t(14;18)(q32;q21) were identified. They ranged in age from 45 to 73 years. The cell type was mixed in four patients, small-cleaved in one, and large-cleaved in one; four cases also contained diffuse areas. All cases tested displayed monoclonal surface Ig. The clinical courses were consistent with the histologic subtypes, being less aggressive than other t(8;14)-bearing NHL. In five cases, frozen tissue was available for Southern blotting. The BCL2 gene showed a germline configuration when studied with the MBR, MCR, and 5' cDNA probes. The MYC gene also appeared unrearranged using an exon-1 probe with EcoRI or HindIII digestion. Analysis of the Ig heavy chain (IgH) gene with a JH region probe and BamHI or EcoRI digestion showed only one rearranged band in all cases, indicating that the 14q32 breakpoint did not lie in either the J or switch-mu (SM) regions. In four cases, the exon-1/intron-1 border of the MYC gene, a target area for point mutations in cases of t(8;14) that do not display rearrangements of the MYC gene, was enzymatically amplified and sequenced; no point mutations were identified. The indolent behavior of our six cases, and the finding that the molecular structure of the t(8;14) in these cases does not follow the pattern of breakpoint sites and point mutations defined in other histologic subtypes of NHL with this translocation, suggest that the t(8;14) in these cases is cytogenetically and molecularly distinct from the t(8;14) seen in high-grade NHLs, and is relatively ineffectual in terms of MYC deregulation, or that other genetic elements at these chromosomal sites may be involved. Further analysis of these tumors may provide insights into MYC deregulation and BCL2-independent FL.
- Published
- 1992
17. MYC rearrangement and translocations involving band 8q24 in diffuse large cell lymphomas.
- Author
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Ladanyi M, Offit K, Jhanwar SC, Filippa DA, and Chaganti RS
- Subjects
- Adult, Blotting, Southern, Deoxyribonucleases, Type II Site-Specific, Exons, Female, Gene Rearrangement, Humans, Male, Middle Aged, Mutation, Polymorphism, Restriction Fragment Length, Restriction Mapping, Translocation, Genetic, Chromosomes, Human, Pair 8, Lymphoma, Large B-Cell, Diffuse genetics, Proto-Oncogene Proteins c-myc genetics
- Abstract
The configuration of the MYC gene in diffuse large cell lymphomas (DLCL) with translocations involving band 8q24 [t(8q24)] has not been systematically studied. We collected cytogenetic and clinical data on 171 consecutive cases of DLCL, including cleaved, noncleaved, and immunoblastic types, of which 96 had DNA available and 124 had abnormal karyotypes. The cases with DNA available were evaluated for MYC rearrangement (MYC-R) by Southern hybridization of EcoRI-digested tumor DNA using an exon-1 probe, a combination of probe and enzyme known to detect over 85% of breaks in sporadic Burkitt's lymphoma. In cases studied at diagnosis, MYC-R, t(8;14)(q24;q32), or other t(8q24) were not prognostically significant. Among the 124 cases with karyotypic abnormalities, seropositivity for human immunodeficiency virus was significantly more common in cases with a t(8q24) (72%) than in cases without it (9%) (P less than .05). Of the four cases with an MYC -R, two had a t(8;14), one had a t(7;8;14)(p15;q24;q32), and one had a t(8;?)(q24;?) and a del(8)(q24). In the three previous cases with translocations involving 8q24 and 14q32, comigration of the rearranged MYC band with either the J region or the switch-mu region of the Ig heavy chain gene could not be demonstrated, leaving the 14q32 breakpoint undefined at the molecular level. Among the remaining 72 cases where both an abnormal karyotype and molecular data were available, 11 had a t(8q24), either t(8;14) or t(8;22)(q24;q11), in the absence of an MYC-R. In these cases, the 8q24 break was presumably located outside of the EcoRI MYC fragment. All 15 cases with a t(8q24) were also screened for point mutations in the PvuII site in the first exon of MYC; two cases that were not MYC-R showed loss of this restriction site. These results indicate that in most DLCL with t(8;14) or other t(8q24), the 8q24 breakpoint lies away from the MYC gene; in a minority of these cases, point mutations in regulatory noncoding regions were detected.
- Published
- 1991
18. Cytogenetic analysis of chimerism and leukemia relapse in chronic myelogenous leukemia patients after T cell-depleted bone marrow transplantation.
- Author
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Offit K, Burns JP, Cunningham I, Jhanwar SC, Black P, Kernan NA, O'Reilly RJ, and Chaganti RS
- Subjects
- Adult, Bone Marrow Cells, Bone Marrow Transplantation immunology, Chromosome Aberrations pathology, Chromosome Disorders, Female, Graft Rejection immunology, Host vs Graft Reaction, Humans, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Philadelphia Chromosome, Prognosis, Transplantation, Homologous, Bone Marrow Transplantation adverse effects, Chimera genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Lymphocyte Depletion
- Abstract
Serial cytogenetic studies were performed on 64 patients with chronic myelogenous leukemia (CML) after T cell-depleted allogeneic bone marrow transplantation (BMT). Forty patients with CML in chronic phase (CP) received cytoreduction followed by BMT with HLA-matched T cell-depleted allogeneic marrow. The remaining 24 patients were transplanted in second chronic, accelerated, or blastic phase, or received T cell-depleted grafts with a dose of T cells added back. The Y chromosome and autosomal heteromorphisms were used to distinguish between donor and host cells. Mixed hematopoietic chimerism (presence of donor and host cells) was identified in 90% of patients in first CP. The Philadelphia (Ph) chromosome reappeared in 16 of the 40 first CP CML patients. As expected, patients who had detectable Ph chromosome positive cells at any time during the posttransplant period had a high likelihood of subsequent clinical relapse. Transient disappearance of the Ph positive clone was rarely observed, and was followed by reappearance of the Ph chromosome or clinical relapse. A subset of engrafted patients with greater than 25% host cells within 3 months post-BMT had a significantly shorter survival time free of cytogenetic or clinical relapse compared with other patients. In patients who had received donor T cells added to the T cell-depleted graft, there was a higher proportion of complete chimerism. Clonal progression of Ph positive as well as negative cells was observed and may be the result of radiation induced breakage. Serial cytogenetic studies of patients post-BMT can provide useful information regarding the biologic and clinical behavior of CML.
- Published
- 1990
19. Specific translocations characterize Burkitt's-like lymphoma of homosexual men with the acquired immunodeficiency syndrome.
- Author
-
Chaganti RS, Jhanwar SC, Koziner B, Arlin Z, Mertelsmann R, and Clarkson BD
- Subjects
- Acquired Immunodeficiency Syndrome complications, Adult, Burkitt Lymphoma complications, Chromosome Aberrations, Chromosomes, Human, 21-22 and Y, Chromosomes, Human, 6-12 and X, Humans, Karyotyping, Male, Acquired Immunodeficiency Syndrome genetics, Burkitt Lymphoma genetics, Homosexuality, Translocation, Genetic
- Abstract
A Burkitt's-like B-cell lymphoma (BLL) has recently been shown to be associated with the acquired immunodeficiency syndrome (AIDS), which affects homosexual men. We report cytogenetic studies of two BLL tumors in homosexual men. Both tumors had chromosome translocations characteristic of Burkitt's lymphoma (BL), one the t(8;14) and the other the t(8;22). The pathway of lymphomagenesis in this disorder is discussed in the light of recent data on chromosome change and localization of immunoglobulin genes and oncogenes.
- Published
- 1983
20. Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes.
- Author
-
Richardson ME, Chen QG, Filippa DA, Offit K, Hampton A, Koduru PR, Jhanwar SC, Lieberman PH, Clarkson BD, and Chaganti RS
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Transformation, Neoplastic genetics, Chromosome Aberrations, Chromosome Disorders, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 7, Female, Humans, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Recurrence, Lymphoma, Non-Hodgkin genetics, Translocation, Genetic
- Abstract
We describe additional nonrandom chromosome abnormalities in 18 cases of intermediate- to high-grade non-Hodgkin's lymphoma (NHL) bearing t(14;18) that were ascertained in a prospective cytogenetic study of all lymphomas seen at Memorial Hospital during the period January 1, 1984, to December 31, 1986. These included seven cases that had histological evidence of transformation from a lower grade and 11 that lacked such evidence. The most common of the additional changes seen in both groups affected chromosomes 6 and 7 and comprised the loss of chromosome 6 or del(6q) and the presence of more than two copies of chromosome 7 or duplication of 7q. Changes affecting these two chromosomes were less frequent in low-grade lymphomas with t(14;18) as well as in lymphomas lacking the translocation. These data suggest that common cytogenetic mechanisms underlie expression of high-grade histologies by lymphomas carrying t(14;18). In addition, they may serve as indicators of transformation when encountered in low-grade lymphomas with t(14;18).
- Published
- 1987
21. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders.
- Author
-
Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, Gay S, and Moore MA
- Subjects
- Adult, Cell Adhesion, Cell Line, Collagen metabolism, Culture Media, Fibrinolysis, Fibroblasts physiology, Fibronectins metabolism, Fluorescent Antibody Technique, Hematopoietic Stem Cells physiology, Humans, Plasminogen Activators metabolism, Bone Marrow physiopathology, Colony-Forming Units Assay, Myeloproliferative Disorders physiopathology
- Abstract
Chronic myeloproliferative disorders (MPD) are clonal diseases of the pluripotent hematopoietic stem cell frequently associated with myelofibrosis (MF). There is only indirect evidence indicating that the increased deposition of collagen in bone marrow matrix is a secondary phenomenon. A liquid culture system for cloning and growing bone marrow fibroblasts has permitted us to approach more directly the understanding of the pathogenesis of myelofibrosis by comparing the biophysical, growth, and functional characteristics of fibroblasts from normals, MPD patients without MF, and those with MF. In patients with MF, marrow fibroblast colony (CFU-F) formation could not be studied; fibroblasts were grown from marrow explants. CFU-E from normals and MPD patients exhibited similar cell density distribution and similar cell sedimentation rates. These similarities contrasted sharply with the differences seen when the erythroid and granulocyte-macrophage progenitors were studied by the same methods. There was a marked light density shift and a rapidly sedimenting shift of MPD hematopoietic colony-forming cells. Marrow fibroblasts from MPD patients with and without MF displayed the same in vitro growth characteristics as fibroblasts from normals. Both types of fibroblasts exhibited anchorage and serum dependence, and contact inhibition of growth. Marrow fibroblasts were also characterized for the presence and distribution of fibronectin and collagen types by immunofluorescent staining using monospecific antibodies. Extracellular matrix, membrane-, and cytoplasm-associated fibronectin, type I, type III, and type V collagen showed a similar staining pattern in both normal and myelofibrotic marrow fibroblasts. Plasminogen-dependent fibrinolytic activity elicited from normal and myelofibrotic marrow fibroblasts were equivalent. Chromosomal analysis of hematopoietic cells and marrow fibroblasts from Philadelphia chromosome positive chronic myelocytic leukemia patients with and without MF showed that the Philadelphia chromosome was present only in hematopoietic cells. The results of these studies taken together demonstrate that bone marrow collagen-producing cells from MPD patients with and without MF behave in vitro as do those from normals. These findings support the hypothesis that that the marrow fibrosis observed in patients with MPD results from a reactive process rather than from a primary disorder affecting the marrow collagen-producing cells.
- Published
- 1982
22. Host origin of the human hematopoietic microenvironment following allogeneic bone marrow transplantation.
- Author
-
Laver J, Jhanwar SC, O'Reilly RJ, and Castro-Malaspina H
- Subjects
- Adolescent, Anemia, Aplastic therapy, Bone Marrow Cells, Cells, Cultured, Child, Hematopoietic Stem Cells cytology, Humans, Karyotyping, Leukemia therapy, Bone Marrow Transplantation, Hematopoiesis
- Abstract
The origin of marrow stromal cells post allogeneic bone marrow transplantation (BMT) was studied. Two groups of patients receiving HLA-identical marrow grafts from sex mismatched siblings were included in the study: the first group (eight patients) received conventional marrow grafts and the second group (ten patients) received stromal cell and T cell depleted grafts. All patients showed hematopoietic engraftment with donor cells. Marrow aspirates obtained from these patients were used to establish stromal layers in long-term marrow cultures (LTMC) for 4 to 6 weeks. In both groups, karyotype analysis of nonhematopoietic cultured stromal cells showed host origin even as late as day 760 posttransplantation. Immunofluorescence methods using monoclonal antibodies against components of fibroblasts, macrophages, and endothelial cells, showed that the composition of stromal layers was similar to those obtained from normal controls. Our data indicate that marrow stromal progenitors capable of proliferation are nontransplantable and do not originate from a hematopoietic-stromal common progenitor.
- Published
- 1987
23. Progression of nodular poorly differentiated lymphocytic lymphoma to Burkitt's-like lymphoma.
- Author
-
Mintzer DM, Andreeff M, Filippa DA, Jhanwar SC, Chaganti RS, and Koziner B
- Subjects
- Adult, Bone Marrow pathology, Burkitt Lymphoma genetics, Burkitt Lymphoma immunology, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic pathology, Chromosome Aberrations genetics, Chromosome Aberrations pathology, Chromosome Disorders, DNA metabolism, Female, Flow Cytometry, Humans, Karyotyping, Kinetics, Lymphoma, Non-Hodgkin genetics, Lymphoma, Non-Hodgkin immunology, Male, Middle Aged, Burkitt Lymphoma pathology, Lymphoma, Non-Hodgkin pathology
- Abstract
Histologic conversion of nodular lymphomas to more aggressive patterns has been well described and occurs in 15% to 40% of cases. Most conversions have involved changes from nodular to diffuse patterns and often from small to larger cell types. Conversions to undifferentiated lymphomas, but not specifically to the Burkitt's type, have infrequently been described. This report describes three cases of nodular poorly differentiated lymphocytic lymphoma that converted to a Burkitt's-like lymphoma. Conversion was associated with short survivals, increasing lactate dehydrogenase (LDH) levels, and changes in DNA stemline, RNA content, and S-phase values, as determined by flow cytometry. Karyotypes in two cases revealed a t(14;18). Surface immunoglobulin could be demonstrated on transformed Burkitt's-like cells from lymph node in one case, but in none of the cases on cells from bone marrow.
- Published
- 1984
24. Cytogenetic and histologic correlations in malignant lymphoma.
- Author
-
Koduru PR, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, and Chaganti RS
- Subjects
- Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Female, Humans, Karyotyping, Lymphoma, Non-Hodgkin classification, Lymphoma, Non-Hodgkin pathology, Male, Translocation, Genetic, Trisomy, Chromosome Aberrations pathology, Lymphoma, Non-Hodgkin genetics
- Abstract
Although a number of studies have indicated correlations between histologic subtypes of tumors and certain nonrandom chromosome changes, cytogenetic studies of lymphoma are in an early stage compared to those of leukemia. No comprehensive analysis of available data has so far been attempted in the literature either. Here we present an analysis of chromosome changes and their correlation with subtypes of lymphoma studied by conventional histology and cell surface markers, as observed in two sets of data: a group of 65 karyotypically abnormal tumors sequentially ascertained and studied by us during the period January 1, 1984 to April 30, 1985, and a larger data set derived by combining our data with those from two published series from the University of Minnesota that are comparable to our data. These combined data, which comprise the largest data set on the cytogenetics of lymphomas assembled so far, enabled a comprehensive analysis of correlation between chromosome change and tumor histology and the patterns of chromosome instability in these tumors. We found several significant associations, some previously described and others now recognized, between nonrandom chromosome gains, breaks, translocations, and deletions and histologic subtypes of tumors that characterize lymphomas. The data indicate that finding of chromosome breaks at certain sites (eg, 8q24, 14q32, 18q21) is of diagnostic value in dealing with cases of unusual lymphoma. Furthermore, nonrandom chromosome breakage exhibited three distinct patterns that reflected three levels of etiologically relevant genetic change.
- Published
- 1987
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