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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequence analysis of a large number of DNA clones containing a functional heavy chain variable, diversity, and joining (VHDJH) complex generated by VH to VHDJH joining (VH gene replacement) in the progeny derived from a common precursor cell transformed with a temperature-sensitive (ts) Abelson murine leukemia virus (A-MuLV) indicates that endogenous VH gene replacement in vitro generates immunoglobulin gene joints distinct from those generated by the usual VH to DJH joining. Such joints keep the pentamer CAAGA at the 3' end of the donor VH segment and lack a recognizable D segment, as can be seen also in vivo. The results suggest that VH gene replacement participates in generating VH region diversity in vivo, as previously postulated. During the joining process, a unique VH gene was selected in all progeny cells, together with a single A nucleotide dominantly added to the junctional boundaries. The basis of these regulatory processes is discussed.
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PMID:Heavy chain variable (VH) region diversity generated by VH gene replacement in the progeny of a single precursor cell transformed with a temperature-sensitive mutant of Abelson murine leukemia virus. 140 63

Discrete rearrangements of immunoglobulin genes are characteristic of lymphoproliferative diseases of B cells and provide direct evidence of their clonal nature. In addition, because leukemic transformation and growth may amplify B cell clones regardless of selection by antigen, analysis of rearranged Ig genes in leukemic clones may give insight into molecular events taking place during the ontogenesis of normal B cells. We have tested DNA samples from patients with chronic B cell leukemias in search for abnormal rearrangements of the Ig heavy chain gene region. By Southern blot analysis we found an unexpected break in the JH-C mu region in 7 out of 118 cases. Two of these cases were investigated in detail by constructing from each a phage genomic library and isolating the phage clones containing the break points. In both cases the JH-C mu separation was confirmed. Further analysis demonstrated that in both cases the abnormality was an inversion of the Ig heavy chain gene between C mu and one of the C gamma segments. This inversion structure strongly suggests that, as has been demonstrated in murine cell lines and in splenocytes stimulated in vitro, class switching in human B lymphocytes occurs in vivo via a loop-out deletion mechanism. The frequency of abnormal events may be as high as 15%. Our data indicate that a proportion of cases of chronic B cell leukemia arise from a cell which has attempted an Ig class switch.
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PMID:Anomalous rearrangements of the immunoglobulin heavy chain genes in human leukemias support the loop-out mechanism of class switch. 146 88

Bone marrow (BM) cells from two transgenic mice carrying the human c-myc oncogene were separately harvested, and each sample was injected into 25 lethally irradiated mice. We observed the contribution of the myc gene to the occurrence of hemopoietic neoplasms in the BM-repopulated mice, establishing a new experimental system for analyzing oncogene expression in the hemopoietic system in vivo. The hybrid gene that was transferred into the original transgenic mice was a combination of the human c-myc gene with a regulatory unit consisting of a murine immunoglobulin-heavy chain with an SV40 early-T promoter gene (Ig/Tp-myc). Among the transgenic lines, the tested BM cells were chosen from two lines that had been low-prone in leukemia; in these lines hemopoietic neoplasms did not appear for greater than or equal 200 days after birth. Lethally irradiated controls received BM cells from litters of transgenic mice that did not carry c-myc. The lifetime incidence of hemopoietic neoplasms was 94% and 91% in the two groups of mice repopulated with myc+ BM. By contrast, only 15% of control mice with myc- BM developed hemopoietic lesions. The incidence of hemopoietic malignancies combined with nonthymic lymphomas and myeloma cases (88% and 65%) was higher in the repopulated mice than the incidence of pre-B cell lymphomas in the original transgenic lines (56%). Thirty-two of the 40 myc+ mice that were examined showed the presence of the transferred gene in either the normal hemopoietic tissue or in the hemopoietic neoplasm. Furthermore, 18 of 22 hemopoietic neoplasms studied by Northern hybridization expressed mRNA from the transgenic gene; in other four neoplasms, expression was weak or absent.
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PMID:Hemopoietic neoplasms in lethally irradiated mice repopulated with bone marrow cells carrying the human c-myc oncogene: a repopulation assay. 154 84

We report the biological characteristics of leukaemic blasts from two cases of acute leukaemia with an interstitial deletion of the long arm of chromosome 9 (9q-). Case 1 (FAB: M1) showed del(9)(q12q22) as the sole karyotypic anomaly, and case 2 (FAB: M1) presented del(9) (q12q22) in association with trisomy 10. In both cases, leukaemic blasts presented unique cytological features, such as prominent vacuoles on Giemsa staining, or strong localization of myeloperoxidase resembling 'pseudo-Chediak-Higashi' granules. Immunophenotyping of blasts revealed the biphenotypic expression of T-lymphoid/myeloid antigens (CD2, CD7/CD33) in addition to CD34. Neither T-cell receptor beta (TCRB), T-cell receptor gamma (TCRG) nor Ig heavy chain (IGH) genes were clonally rearranged. Furthermore, there was neither rearrangement nor expression of ABL, which is located at 9q34, indicating that the deletion involved bands centrometric to 9q34 did not induce the activation of ABL. DNA synthesis of the blasts was stimulated (stimulation index greater than 2.0) in the presence of interleukin (IL)-3, IL-4, granulocyte colony-stimulating factor or erythropoietin (Epo). IL-3 and IL-4 could also support the in vitro growth of leukaemic blast colonies, and the IL-3- or IL-4-dependent blast colony growth was synergistically enhanced by the addition of IL-6 or Epo. These observations imply that T-lymphoid/myeloid or pluripotent stem cells may be closely involved in the development of 9q- AML.
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PMID:Interstitial 9q deletion in T-lymphoid/myeloid biphenotypic leukaemia. 155 Jul 72

Natural autoantibodies are primarily immunoglobulin M (IgM) antibodies that bind to a variety of self-antigens, including self-IgG. Accounting for a large proportion of the early B cell repertoire, such polyspecific autoantibodies are speculated to contribute to the homeostasis and/or competence of the primary humoral immune system. Recent studies indicate that the leukemia cells from most patients with chronic lymphocytic leukemia (CLL) also express such IgM autoantibodies. Similarly, the leukemia cells from many CLL patients react with murine monoclonal antibodies (mAbs) specific for crossreactive idiotypes (CRIs) associated with human IgM autoantibodies. In particular, leukemic cells frequently react with G6, a mAb specific for an Ig heavy chain (H chain)-associated CRI, and/or with 17.109, a mAb that defines a kappa light chain (L chain)-associated CRI. Generated against IgM rheumatoid factor (RF) paraproteins, G6 and 17.109 each recognize a major CRI that is present in many IgM RF paraproteins. Furthermore, over 90% of the IgM paraproteins found to bear both H and L chain-associated CRIs also are found to have RF activity. Molecular characterization of these CRIs demonstrates that each is a serologic marker for expression of a highly conserved Ig V gene. As such, the frequent production of IgM polyspecific autoantibodies in CLL simply may reflect the frequent use of such highly conserved autoantibody-encoding Ig V genes with little or no somatic mutation. To test this hypothesis, we generated murine transfectomas to pair the 17.109-reactive kappa L chain of SMI, a 17.109/G6-reactive CLL population, with the Ig H chain of SMI or other G6-reactive leukemia cells or tonsillar lymphocytes. Cotransfection of vectors encoding the Ig H and L chains of SMI generated transfectomas that produce IgM kappa RF autoantibodies reactive with human IgG1 and IgG4. In contrast to G6/17.109-reactive IgM kappa RF Waldenstrom's paraproteins, the SMI IgM kappa also reacts with several other self-antigens, including myoglobin, actin, and ssDNA. However, cotransfection of the SMI L chain with a vector encoding any one of 10 different G6-reactive Ig H chains generated transfectomas that produce IgM kappa antibodies without detectable polyspecific autoantibody activity. These results indicate that polyspecific antiself-reactivity of G6/17.019-reactive Ig is dependent on the somatically generated Ig third complementarity determining region. Collectively, these studies imply that selection may be responsible for the frequent expression of polyspecific autoantibodies in CLL and early B cell ontogeny.
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PMID:Evidence for somatic selection of natural autoantibodies. 155 91

Rearrangements of the heavy chain immunoglobulin gene and T cell receptor beta gene were investigated in 25 patients suffering from precursor B cell acute leukaemia and six patients suffering from T cell acute leukaemia using biotinylated DNA probes. All precursor B acute leukaemia patients had IgH gene rearrangements and 63% of those studied also had TCR beta gene rearrangements. All T cell acute leukaemia patients had TCR beta gene rearrangements and germline IgH configuration. Dilution experiments indicated that DNA from leukaemic cells representing 1-2% of a tested sample could be detected using this technique which compares favourably to radioactive DNA probes.
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PMID:Non-radioactive detection of immunoglobulin and T cell receptor gene rearrangement in acute lymphoblastic leukaemia. 166 Nov 25

Immunoglobulin heavy and light chain genes undergo rearrangement before they can be expressed by B-cells. A sequence of successive rearrangements has been proposed, suggesting that these events are initiated on heavy chain genes and are followed by sequential attempts of light chain gene rearrangements involving kappa gene alleles before lambda genes. This hypothesis, mainly established on B-cell clones of medullary origin, is consistent with the predominance of kappa chains among human serum immunoglobulins. However, data from tumors or normal lymphoid tissue suggest that lambda chain expression could be favored outside the bone marrow, due to an alternative rearrangement hierarchy. We investigated this hypothesis further on 17 leukemia samples. In three instances, we observed that lambda genes had undergone rearrangement while kappa genes remained in germline configuration. These data support the hypothesis of occasional alternative rearrangements of light chain genes.
Leukemia 1991 Aug
PMID:Alternative rearrangements of immunoglobulin light chain genes in human leukemia. 167 70

Detailed immunophenotypic analyses of immunologically classified leukemias and lymphomas showed that CD40 displays an exquisite B-lineage specificity within the human lymphopoietic system. Notably, 82% of B-lineage chronic lymphocytic leukemias (CLLs), 82% of B-lineage hairy cell leukemias (HCLs), 86% of B-lineage non-Hodgkin's lymphomas (NHLs), and 29% of B-lineage acute lymphoblastic leukemias (ALLs) were CD40+. Quantitative analyses of the correlated expression of CD40 and other B-lineage differentiation antigens on fetal lymphoid precursor cells by multiparameter two-color/three-color flow cytometry, combined with analyses of sequential antigen expression on fluorescence-activated cell fluorescence activated cell sorter (FACS) isolated immunologically distinct fetal B-cell precursor subpopulations during in vitro proliferation and differentiation, provided evidence that the acquisition of CD40 antigen in human B-cell ontogeny occurs subsequent to the expression of CD10 and CD19 antigens but before the surface expression of CD20, CD21, CD22, CD24, and surface immunoglobulin M (sIgM). Some leukemic pro-B cells from ALL patients as well as normal pro-B cell clones from fetal livers displaying germline Ig heavy chain genes were CD40+, indicating that the acquisition of CD40 antigen likely precedes the rearrangement of Ig heavy chain genes. CD40+ FACS-sorted malignant cells from B-lineage ALL as well as B-lineage NHL patients were capable of in vitro clonogenic growth, indicating the CD40 antigen is expressed on clonogenic leukemia and lymphoma cells. This hypothesis was confirmed by the ability of an anti-CD40 immunotoxin that we used as an antigen-specific cytotoxic probe to effectively kill clonogenic B-lineage ALL and NHL cells.
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PMID:Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells. 170 26

We studied the expression of cell surface antigens associated with myeloid and lymphoid leukemias on bone marrow-derived blast cells from 339 patients with newly diagnosed de novo acute myeloid leukemia (AML) enrolled on Cancer and Leukemia Group B (CALGB) chemotherapy protocols. Surprisingly, of 211 cases studied for the expression of CD2 (T-cell marker, sheep erythrocyte binding receptor for T lymphocytes) 45 were positive (21%). In addition, of 298 patients studied for CD19 (B-lymphocyte marker), 41 were positive (14%). Overall, of 170 patients studied for both CD2 and CD19, 56 (33%) were positive. Interestingly, central review of the French-American-British (FAB) morphology of the CD2- and CD19-positive cases showed that FAB M3 was twice as frequent, and M4E eight times as frequent compared with the CD2- and CD19-negative cases. Of 22 lymphocyte antigen-positive cases in which cells were available for studies of Ig or T-cell antigen receptor (TCR) gene rearrangement, 20 were germline, one had a rearranged Ig heavy chain gene, and one had rearranged TCR beta and Ig heavy chain genes. The presence of messenger RNA for CD2 was demonstrated in four CD2 surface antigen-positive cases, thus validating the cell surface data. Lymphocyte antigen-positive cases had karyotypes commonly seen in AML; 71% of cases with an abnormal clone had t(8;21)(q22;q22), inversion 16(p13q22), t(15;17)(q22;q12), or t(9;11)(p22;q23). The patients with lymphocyte markers had a significantly higher incidence of these karyotypic abnormalities compared with patients with lymphocyte antigen-negative AML (34% v 15%, P less than .02). When the outcome to therapy of the lymphocyte antigen-positive cases was compared with that for the CD2, CD19-negative cases, we found that the CD2, CD19-positive cases actually had higher complete remission rates (75% v 59%, P = .04), and significantly longer time to failure (P = .02; 32.4% +/- 6.0% v 18.0% +/- 4.1% at 2 years) and overall survival (P = .02; 43.5% +/- 6.3% v 26.0% +/- 4.5% at 2 years). CD2 antigen-positive cases also had a significantly superior survival (P = .02; 43.8% +/- 7.9% v 29.8% +/- 3.8% at 2 years). There were no significant differences (P less than or equal to .05) between the two groups in age, leukocyte count at diagnosis, incidence of extramedullary disease, or FAB classification.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prognostic value of lymphocyte surface markers in acute myeloid leukemia. 137 22

We previously documented that a single BCL1 leukemia cell can produce mu and gamma 1 immunoglobulin heavy chains with identical variable segments in an allelically excluded fashion without heavy chain constant region gene rearrangement. To understand the mechanism of dual mu/gamma 1 synthesis in BCL1 subclones, we have analyzed mature and pre-RNA at the nascent and steady-state levels. We find mu and gamma 1 sequences linked in pre-RNA. However, the primary mu and gamma 1 transcription units are about the same length (approximately 15 kilobases). Initiation of gamma 1 pre-RNA occurs upstream of C gamma 1 at sites identical to those seen in lipopolysaccharide/interleukin-4-induced normal B cells. We propose that dual mu/gamma 1 RNA synthesis occurs by a discontinuous transcription mechanism involving either trans-splicing or ligation of mu pre-RNA initiated 5' of the variable-diversity-joining region to gamma 1 pre-RNA initiated 5' of C gamma 1.
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PMID:Coexpression of mu and gamma 1 heavy chains can occur by a discontinuous transcription mechanism from the same unrearranged chromosome. 174 77


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