scholarly journals Advancement of multiple myeloma from diagnosis through plateau phase to progression does not involve a new B-cell clone: evidence from the Ig heavy chain gene

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 202-206 ◽  
Author(s):  
QM Ralph ◽  
MJ Brisco ◽  
DE Joshua ◽  
R Brown ◽  
J Gibson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Heavy Chain ◽  
Cell Clone ◽  
Neoplastic Cell ◽  
Chain Gene ◽  
Plateau Phase ◽  
Igh Genes ◽  
Igh Rearrangement ◽  
Ig Heavy Chain

The Ig heavy chain (IgH) gene was used as a marker to investigate clonal succession and the origin of the neoplastic cell in multiple myeloma. The polymerase chain reaction (PCR) was used to amplify a section of the rearranged IgH gene at diagnosis and at progression in 21 patients who had exhibited a plateau phase. A monoclonal PCR product was seen for 16 of the patients and the product present at progression was of the same molecular weight as that at diagnosis. This finding suggests that the IgH rearrangement present at diagnosis and progression was the same. This was confirmed by sequencing the IgH gene in 10 patients. The IgH genes were found to be hypermutated at diagnosis, but no further hypermutation occurred during the course of the disease. The results provide evidence that the neoplastic cell in myeloma may originate as a memory B cell, plasmablast, or plasma cell, and suggest that progression beyond the plateau phase is not caused by clonal succession.

scholarly journals Immunoglobulin and T cell receptor gene configuration in acute lymphoblastic leukemia of infancy

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 536-541 ◽  
Author(s):  
CA Felix ◽  
GH Reaman ◽  
SJ Korsmeyer ◽  
GF Hollis ◽  
PA Dinndorf ◽  
...  
Keyword(s):  
B Cell ◽  
T Cell Receptor ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Cell Precursor ◽  
Ig Heavy Chain

Abstract We examined immunoglobulin (Ig) heavy chain, K light chain, and T cell receptor (TCR) gamma and beta gene configuration in the leukemic cells from a series of infants aged less than 1 year with acute lymphoblastic leukemia (ALL). Each of these 11 cases demonstrated leukemic cell surface antigens that have been correlated with a B cell precursor phenotype. Of the 11, lymphoblasts of 4 retained the germline configuration of both Ig and TCR loci, whereas 7 had rearranged the Ig heavy chain gene. Two of these seven showed light chain gene rearrangement. TCB beta chain rearrangement had occurred in only one of the 11 patients' tumors. No TCR gamma chain rearrangements were identified. These results are in contrast to earlier studies of B cell precursor ALL in children in which Ig heavy chain gene rearrangements were evident in every case and approximately 40% showed Ig light chain rearrangement as well. In addition, 45% of cases of B cell precursor ALL of children had rearranged their gamma TCR genes, and 20% had rearranged beta. These data suggest that ALL in infancy represents an earlier stage of B cell development than is found in B cell precursor ALL of children. ALL in the infant age group has been associated with the worst prognosis of all patients with ALL. This study suggests that the disease in infants differs not only clinically, but also at the molecular genetic level, from the disease in children.

Ambiguous phenotypes and genotypes in 16 children with acute leukemia as characterized by multiparameter analysis

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1518-1528
Author(s):  
WD Ludwig ◽  
CR Bartram ◽  
J Ritter ◽  
A Raghavachar ◽  
W Hiddemann ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Gene Rearrangement ◽  
Molecular Genetic ◽  
Surface Marker ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Ig Heavy Chain

Ambiguous phenotypes and genotypes were observed in 16 children with acute leukemia. Surface marker, cytogenetic, molecular genetic, and DNA flow cytometric analyses as well as standard morphologic and cytochemical studies were used to divide the patients into three groups. The first group comprised five children with acute leukemia whose blast cells were morphologically lymphoid, while immunophenotyping disclosed simultaneous expression of early pre-B cell and myeloid features. Molecular genetic studies showed evidence of heavy-chain immunoglobulin (Ig) gene rearrangements in all patients. Cytogenetic data, available in three of these children, revealed t(4;11). In five of the 16 patients, morphologic and surface marker analyses indicated the coexistence of two separate cell populations, one with myeloid and the other with early pre-B cell features. Further evidence of B cell commitment in these patients was provided by demonstration of Ig heavy-chain gene rearrangements in all five patients. Surprisingly, one of the five patients showed oligoclonal Ig heavy-chain as well as monoclonal gene rearrangement for the beta chain of the T cell receptor (beta-TCR). The last group consisted of four cases with otherwise typical acute lymphoblastic leukemia (ALL), early pre-B cell phenotype, and coexpression of myeloid or T cell-associated antigens, and two children with unequivocal acute myeloid leukemia (AML) and coexpression of T cell antigens. Gene rearrangement of Ig heavy-chain could be demonstrated in five of six patients, additional Ig light-chain gene rearrangement in two children with ALL, and bigenotypic features (Ig heavy-chain and beta-TCR gene rearrangement) in one patient. In none of the 16 patients did flow cytometry disclose clonal abnormalities of leukemic cell DNA content. Based on these findings, we suggest that malignant transformation in the first and second group of patients took place at a stage ontogenetically close to the pluripotent stem cell, whereas ambiguous phenotypes in the third group resulted from aberrant gene expression or insufficient reagent specificity.

scholarly journals Coordination of immunoglobulin DJH transcription and D-to-JH rearrangement by promoter-enhancer approximation.

1991 ◽  
Vol 11 (4) ◽  
pp. 2096-2107 ◽  
Author(s):  
A Alessandrini ◽  
S V Desiderio
Keyword(s):  
Steady State ◽  
B Cell ◽  
Heavy Chain ◽  
Progenitor Cell ◽  
Cell Clone ◽  
Transcriptional Start Site ◽  
Gene Segment ◽  
Coding Region ◽  
Variable Regions ◽  
Ig Heavy Chain

The genes that encode the variable regions of immunoglobulin (Ig) heavy chains are encoded by three DNA segments: VH, D, and JH. During B-cell development these segments are brought together by a pair of site-specific DNA rearrangements. The first of these joins a D segment to a JH segment; the second brings a VH segment in apposition to a DJH unit. B-cell precursors that have undergone D-to-JH joining express transcripts that initiate at the 5' flanks of rearranged D segments (DJH transcription). In this study we have examined the coordination of D-to-JH rearrangement and DJH transcription. The B-lymphoid progenitor cell line HAFTL-1 cell clone, joining of distal D segments (DSP2 and DFL16) to JH is accompanied by an increase in the steady-state level of transcripts initiating 5' of the D coding region. Steady-state transcription of a DSP2 gene segment was undetectable prior to rearrangement and was observed to increase at least 20-fold upon joining to JH. In contrast, transcription from the 5' flank of DQ52, which lies within 700 bp of the JH cluster, was detected prior to rearrangement and did not increase significantly after rearrangement. The 5' flank of a DSP2 segment was found to support expression of a heterologous gene upon transfection into B progenitor cell lines. Expression from this DSP2 promoter was at least 30-fold higher in the presence of the Ig heavy-chain enhancer, in either orientation, than in its absence. A DNA fragment spanning the interval from -165 to +19 bp relative to the major DSP2 transcriptional start site retained enhancer-dependent promoter activity. These observations imply that activation of DSP12JH and DFL16JH transcription is coordinated with D-to-JH rearrangement by approximation of enhancer-dependent D promoter elements to the Ig heavy-chain enhancer. This interpretation is consistent with our observation that the DQ52 segment, which is closely linked to the JH cluster, is transcribed both before and after rearrangement.

FISH Analysis of IgH Rearrangement by 4 Kinds of Probes Involving IgH Genes in Multiple Myeloma: Improved Sensitivity for the Detection by Use of IGH Break-Apart Probe.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4134-4134
Author(s):  
Hye Yoon Chung ◽  
Miyoung Kim ◽  
Cha Ja See ◽  
Hyun Jung Min ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Gene Rearrangement ◽  
Chain Gene ◽  
Fish Analysis ◽  
Dual Color ◽  
Igh Genes ◽  
Detectable Rate ◽  
Igh Gene Rearrangement ◽  
Chain Gene Rearrangement ◽  
Igh Rearrangement

Abstract Background: IgH (immunoglobulin heavy chain) gene rearrangement is known to be the most frequent chromosome change in multiple myeloma. The detection of this genetic change is conveniently done by using fluorescence in situ hybridization (FISH) method recently. The aim of this study is to determine the utility of most commonly used probes, IGH/CCND1 dual color, dual fusion probe (Downers Grove, IL, USA), IGH/BCL2 dual color, dual fusion probe (Downers Grove, IL, USA), IGH/FGFR3 dual color, dual fusion probe (Downers Grove, IL, USA) and IGH dual color break apart rearrangement probe from Vysis Products (Downers Grove, IL, USA). Methods: We applied four different probes of IgH FISH on 202 Korean patients with multiple myeloma for comparing the utility of four probes. Results: 84 of 202 patients (41.6%) had the IgH gene rearrangement. 44 of 84 patients (52.4%) showed positive to all four probes, but 40 of 84 patients (47.6%) showed discrepancy. IGH dual color break apart rearrangement probe showed highly detectable rate (41.6%) compare to IGH/CCND1 (31.2%), IGH/BCL2 (27.7%) and IGH/FGFR3 (24.3%). Among patients who showed discrepancy between four probes, 20 of 40 patients (50.0%) were only positive to IGH dual color break apart rearrangement probe. Conclusions: The IGH break-apart probe was qualitatively and quantitatively better than three other probes at initial diagnosis and during follow-up of myeloma. In conclusion, it would be most efficient and advisable to use the IGH break-apart probe at first, and then to identify the translocation partner in case of positive rearrangement of IgH.

scholarly journals The Ig Heavy Chain Gene Is Frequently Involved in Chromosomal Translocations in Multiple Myeloma and Plasma Cell Leukemia as Detected by In Situ Hybridization

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 526-534 ◽  
Author(s):  
Kazuhiro Nishida ◽  
Akiko Tamura ◽  
Naozo Nakazawa ◽  
Yutaka Ueda ◽  
Tatsuo Abe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
Plasma Cell ◽  
Heavy Chain ◽  
Plasma Cell Leukemia ◽  
Critical Event ◽  
Chain Gene ◽  
Cell Leukemia ◽  
Ig Heavy Chain

Abstract Chromosome rearrangement of 14q32.33 has recurrently occurred with variable partner sites, including 11q13.3, 8q24.1, 18q21.3, and 6p21.1 in multiple myeloma (MM). To assess the actual incidence of 14q32.33 translocation and to elucidate its implication in the pathogenesis of MM, we studied 42 patients with MM, plasma cell leukemia, or plasmacytoma and 5 with monoclonal gammopathy with undetermined significance (MGUS) by G-banding and molecular cytogenetic methods. Using double-color fluorescence in situ hybridization (DCFISH) with 2 Ig heavy chain (IgH) gene probes, a yeast artificial chromosome (YAC) clone containing variable region, and a phage clone containing γ constant region, 14q32.33 translocation was detected as split signals of the IgH gene in 31 patients with plasma cell malignancies and 3 with MGUS. In contrast, of 40 patients who were assessed by G-banding, 3 (7.5%) showed the 14q+ chromosome. DCFISH detected a split of the IgH gene on interphase nuclei in 34 (73.9%) of 46 patients analyzed, whereas on metaphase spreads, it was in 22 (51.2%) of 43 patients analyzed. Interphase DCFISH was particularly useful to detect 14q32.33 translocation in 17 (65.4%) of 26 patients with normal karyotypes. Donor sites were identified in 11 of 22 patients demonstrated as carrying 14q32.33 translocation by metaphase FISH. Chromosome t(11; 14)(q13.3; q32.33) was detected in 5 patients, t(8; 14)(q24.1; q32.33) in 2, t(14; 18)(q32.33; q21.3) in 2, and t(7; 14)(q32.1; q32.33) in 1. A complex 14q32.33 translocation involving 3q and 16q24 was detected in 1 patient. Myeloma cells with t(7; 14) showed myelomonocytoid surface antigen. Because rearrangements of 14q32.33 were closely associated with translocation of proto-oncogenes into the IgH gene, our findings indicate that 14q32.33 translocation with various partner chromosomes is a critical event in the pathogenesis of MM and MGUS.

scholarly journals Surface phenotype and Ig heavy-chain gene usage in chronic B-cell leukemias: expression of myelomonocytic surface markers in CD5- chronic B-cell leukemia

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2602-2610 ◽  
Author(s):  
W Ikematsu ◽  
H Ikematsu ◽  
S Okamura ◽  
T Otsuka ◽  
M Harada ◽  
...  
Keyword(s):  
Gene Family ◽  
B Cell ◽  
Heavy Chain ◽  
Antigen Expression ◽  
Leukemic Cells ◽  
Chain Gene ◽  
Present Observation ◽  
Similar Frequency ◽  
Vh Gene ◽  
Ig Heavy Chain

Abstract We investigated the surface expression of leukocyte differentiation antigens and the Ig heavy-chain variable region (VH) gene family use in leukemic cells from 26 Japanese patients with chronic B-cell leukemias with special reference to CD5 antigen expression. CD5 was expressed on leukemic cells in 21 of 26 cases (CD5+) but not in 5 cases (CD5-). Myelomonocytic marker, CD13 antigen was expressed on the leukemic cells in all 5 CD5- cases but in none of CD5+ cases. Leukemic cells in CD5- cases also expressed CD11b antigen more frequently than those in CD5+ cases (80% v 11%; P < .01). Another myeloid marker, CD33, was expressed neither on CD5+ nor CD5- leukemic cells. CD22, a restricted B-cell marker, was expressed more frequently on CD5- leukemic cells than on CD5+ leukemic cells (80% v 33%; P < .05). Another restricted B-cell activation marker, CD23, was expressed at similar frequency in both the CD5+ and CD5- groups (67% v 60%). Although CD45RA was expressed on the majority of leukemic B cells, the CD45RA expression level was significantly higher among CD5- cases than CD5+ cases (P < .01). In the analysis of VH gene expressed in chronic B-cell leukemias by polymerase chain reaction amplification, CD5+ cases preferentially used VH4 family members (48%; 10 of 21). CD5- cases, on the other hand, mainly used VH3 family (80%; 4 of 5). Thus, from our present observation of an albeit limited patient population, we have found an association between VH gene family use and CD5 antigen expression in chronic B-cell leukemias. We have also shown the differential expression of myelomonocytic markers in the CD5+ and CD5- chronic B-cell leukemias. These result are in agreement with previous suggestions that CD5 positivity is the hallmark for distinct clinical entity commonly referred to in the literature as chronic lymphocytic leukemia.

scholarly journals The Ig Heavy Chain Gene Is Frequently Involved in Chromosomal Translocations in Multiple Myeloma and Plasma Cell Leukemia as Detected by In Situ Hybridization

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 526-534 ◽  
Author(s):  
Kazuhiro Nishida ◽  
Akiko Tamura ◽  
Naozo Nakazawa ◽  
Yutaka Ueda ◽  
Tatsuo Abe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
Plasma Cell ◽  
Heavy Chain ◽  
Plasma Cell Leukemia ◽  
Critical Event ◽  
Chain Gene ◽  
Cell Leukemia ◽  
Ig Heavy Chain

Chromosome rearrangement of 14q32.33 has recurrently occurred with variable partner sites, including 11q13.3, 8q24.1, 18q21.3, and 6p21.1 in multiple myeloma (MM). To assess the actual incidence of 14q32.33 translocation and to elucidate its implication in the pathogenesis of MM, we studied 42 patients with MM, plasma cell leukemia, or plasmacytoma and 5 with monoclonal gammopathy with undetermined significance (MGUS) by G-banding and molecular cytogenetic methods. Using double-color fluorescence in situ hybridization (DCFISH) with 2 Ig heavy chain (IgH) gene probes, a yeast artificial chromosome (YAC) clone containing variable region, and a phage clone containing γ constant region, 14q32.33 translocation was detected as split signals of the IgH gene in 31 patients with plasma cell malignancies and 3 with MGUS. In contrast, of 40 patients who were assessed by G-banding, 3 (7.5%) showed the 14q+ chromosome. DCFISH detected a split of the IgH gene on interphase nuclei in 34 (73.9%) of 46 patients analyzed, whereas on metaphase spreads, it was in 22 (51.2%) of 43 patients analyzed. Interphase DCFISH was particularly useful to detect 14q32.33 translocation in 17 (65.4%) of 26 patients with normal karyotypes. Donor sites were identified in 11 of 22 patients demonstrated as carrying 14q32.33 translocation by metaphase FISH. Chromosome t(11; 14)(q13.3; q32.33) was detected in 5 patients, t(8; 14)(q24.1; q32.33) in 2, t(14; 18)(q32.33; q21.3) in 2, and t(7; 14)(q32.1; q32.33) in 1. A complex 14q32.33 translocation involving 3q and 16q24 was detected in 1 patient. Myeloma cells with t(7; 14) showed myelomonocytoid surface antigen. Because rearrangements of 14q32.33 were closely associated with translocation of proto-oncogenes into the IgH gene, our findings indicate that 14q32.33 translocation with various partner chromosomes is a critical event in the pathogenesis of MM and MGUS.

scholarly journals Surface phenotype and Ig heavy-chain gene usage in chronic B-cell leukemias: expression of myelomonocytic surface markers in CD5- chronic B-cell leukemia

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2602-2610
Author(s):  
W Ikematsu ◽  
H Ikematsu ◽  
S Okamura ◽  
T Otsuka ◽  
M Harada ◽  
...  
Keyword(s):  
Gene Family ◽  
B Cell ◽  
Heavy Chain ◽  
Antigen Expression ◽  
Leukemic Cells ◽  
Chain Gene ◽  
Present Observation ◽  
Similar Frequency ◽  
Vh Gene ◽  
Ig Heavy Chain

We investigated the surface expression of leukocyte differentiation antigens and the Ig heavy-chain variable region (VH) gene family use in leukemic cells from 26 Japanese patients with chronic B-cell leukemias with special reference to CD5 antigen expression. CD5 was expressed on leukemic cells in 21 of 26 cases (CD5+) but not in 5 cases (CD5-). Myelomonocytic marker, CD13 antigen was expressed on the leukemic cells in all 5 CD5- cases but in none of CD5+ cases. Leukemic cells in CD5- cases also expressed CD11b antigen more frequently than those in CD5+ cases (80% v 11%; P < .01). Another myeloid marker, CD33, was expressed neither on CD5+ nor CD5- leukemic cells. CD22, a restricted B-cell marker, was expressed more frequently on CD5- leukemic cells than on CD5+ leukemic cells (80% v 33%; P < .05). Another restricted B-cell activation marker, CD23, was expressed at similar frequency in both the CD5+ and CD5- groups (67% v 60%). Although CD45RA was expressed on the majority of leukemic B cells, the CD45RA expression level was significantly higher among CD5- cases than CD5+ cases (P < .01). In the analysis of VH gene expressed in chronic B-cell leukemias by polymerase chain reaction amplification, CD5+ cases preferentially used VH4 family members (48%; 10 of 21). CD5- cases, on the other hand, mainly used VH3 family (80%; 4 of 5). Thus, from our present observation of an albeit limited patient population, we have found an association between VH gene family use and CD5 antigen expression in chronic B-cell leukemias. We have also shown the differential expression of myelomonocytic markers in the CD5+ and CD5- chronic B-cell leukemias. These result are in agreement with previous suggestions that CD5 positivity is the hallmark for distinct clinical entity commonly referred to in the literature as chronic lymphocytic leukemia.

scholarly journals Coordination of immunoglobulin DJH transcription and D-to-JH rearrangement by promoter-enhancer approximation

1991 ◽  
Vol 11 (4) ◽  
pp. 2096-2107 ◽  
Author(s):  
A Alessandrini ◽  
S V Desiderio
Keyword(s):  
Steady State ◽  
B Cell ◽  
Heavy Chain ◽  
Progenitor Cell ◽  
Cell Clone ◽  
Transcriptional Start Site ◽  
Gene Segment ◽  
Coding Region ◽  
Variable Regions ◽  
Ig Heavy Chain

The genes that encode the variable regions of immunoglobulin (Ig) heavy chains are encoded by three DNA segments: VH, D, and JH. During B-cell development these segments are brought together by a pair of site-specific DNA rearrangements. The first of these joins a D segment to a JH segment; the second brings a VH segment in apposition to a DJH unit. B-cell precursors that have undergone D-to-JH joining express transcripts that initiate at the 5' flanks of rearranged D segments (DJH transcription). In this study we have examined the coordination of D-to-JH rearrangement and DJH transcription. The B-lymphoid progenitor cell line HAFTL-1 cell clone, joining of distal D segments (DSP2 and DFL16) to JH is accompanied by an increase in the steady-state level of transcripts initiating 5' of the D coding region. Steady-state transcription of a DSP2 gene segment was undetectable prior to rearrangement and was observed to increase at least 20-fold upon joining to JH. In contrast, transcription from the 5' flank of DQ52, which lies within 700 bp of the JH cluster, was detected prior to rearrangement and did not increase significantly after rearrangement. The 5' flank of a DSP2 segment was found to support expression of a heterologous gene upon transfection into B progenitor cell lines. Expression from this DSP2 promoter was at least 30-fold higher in the presence of the Ig heavy-chain enhancer, in either orientation, than in its absence. A DNA fragment spanning the interval from -165 to +19 bp relative to the major DSP2 transcriptional start site retained enhancer-dependent promoter activity. These observations imply that activation of DSP12JH and DFL16JH transcription is coordinated with D-to-JH rearrangement by approximation of enhancer-dependent D promoter elements to the Ig heavy-chain enhancer. This interpretation is consistent with our observation that the DQ52 segment, which is closely linked to the JH cluster, is transcribed both before and after rearrangement.

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