Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients

Billadeau, Daniel D.; Quam, Lois; Thomas, William K.; Kay, NE; Greipp, Philip R.; Kyle, RA; Oken, MM; Ness, Brian Van

doi:10.1182/blood.v80.7.1818.1818

Cited by 164 publications

(43 citation statements)

References 23 publications

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“…Average size of N1 and N2 in adult B cells has been previously investigated by sequence analysis of 99 VNDNJ alleles from six normal individuals (Yamada et al, 1991) as well as in ALL (Deane & Norton, 1991) and no significant differences in size of N1 and N2 regions have been observed (P 0 : 134). This was consistent with sequence analysis of other forms of chronic leukaemia (CLL, MM and NHL) (Billadeau et al, 1992;Linke et al, 1995).…”

Section: Discussionsupporting

confidence: 83%

“…No systematic comparison of the structural features of the IgH rearranged region in adult and childhood ALL has been presented, although sequence analyses have been reported in the past few years from over 200 cases with various acute and chronic leukaemias (Billadeau et al, 1992;Deane & Norton, 1990;Ito et al, 1993;Jonsson et al, 1990;Kitchingman, 1993Kitchingman, , 1994Potter et al, 1992Potter et al, , 1993Steenbergen et al, 1993;Steward et al, 1992;Wasserman et al, 1992a, b). Structural difference (e.g.…”

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confidence: 99%

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Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia

et al. 1996

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Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of cases of B-lineage acute lymphoblastic leukaemia (ALL). We have examined bone marrow samples taken at presentation or relapse from 109 patients (79 adults and 30 children) and have performed sequence analysis of the complementarity determining region 3 (CDR3) on 65 alleles from 54 patients. We aimed to define immunoglobulin heavy chain (IgH) variable segment family use and investigate biological and structural features of the B cell in adult and childhood ALL. Using the FR1 fingerprinting method, a rearranged band was identified in 70 (89%) of 79 adult ALL and in 29 (97%) of 30 childhood ALL. This study found no preferential use or selection of IgH VH genes and no statistically significant structural differences between normal and leukaemic B cells in either adult and childhood ALL. An equal proportion of amplifiable cases of adult and childhood ALL uses more than one VH family gene (24/70, 34%, and 8/29, 27.5%, respectively). There were no significant differences in the structure or size of the CDR3 region and the variable (V) or joining (J) segment use in ALL patients compared to normal B cells. We observed that the N2 region was shorter than N1 in children whereas the opposite was observed in adults (not statistically significant). The J4 segment was a more common rearrangement in children than in adults, and in both groups J4 was more frequently associated with multiple D segment VDJ rearrangements. An increase in VH6 use in leukaemic alleles compared to normal B lymphocytes (2%) was observed but it was not statistically significant in our group of patients. Amongst children and adults, in-frame CDR3 junctions occurred in 78% and 64% of rearranged alleles, respectively, compared to 75% of in-frame sequences reported by others to occur among normal B cells.

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Section: Discussionsupporting

confidence: 83%

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confidence: 99%

Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia

et al. 1996

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“…In contrast, our results are in better agreement with those of Smadja et al (1995) who showed that the detection of chromosomal abnormalities in MM was higher in unstimulated day 3 BM cultures than in day 6 cultures stimulated with IL-6 + GM-CSF. The detection of ploidy abnormalities (Zandecki et al, 1994;Drach et al, 1995) and the presence of Ig genes rearrangement in circulating B cells similar to those of malignant PC suggest that at least a subpopulation of B cells belong to the malignant clone (Billadeau et al, 1992;Pilarski et al, 1994;Witzig, 1994) and could represent the proliferating and maturing clonal compartment. Based on this hypothesis, we tried to recruit clonal prePC precursors by using, in addition to IL-6 and GM-CSF, IL-2, IL-4 and TNFa to induce their proliferation Sawamura et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic study of 30 patients with multiple myeloma: comparison of 3 and 6 day bone marrow cultures stimulated or not with cytokines by using a miniaturized karyotypic method

et al. 1997

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Summary. Cytogenetics in multiple myeloma (MM) cases are generally difficult to perform due to the low proliferation index of malignant plasma cells (PC) in most cases. Although IL-6 and GM-CSF stimulate the in vitro proliferation of malignant plasma cells, their usefulness for improving cytogenetic results in multiple myeloma patients remains questionable, because results which compare various culture conditions in a sufficient number of patients are not available. By using a miniaturized karyotypic method, we compared in 30 multiple myeloma patients the number and percentage of clonal abnormal mitoses obtained from 3 and 6 d bone marrow cultures performed without or with two combinations of cytokines: IL-6 þ GM-CSF or IL-6 þ GM-CSF þ IL-2 þ IL-4 þ TNFa. The percentage of patients with an abnormal karyotype, which varied with the Durie and Salmon stage of the disease, as well as the type of numerical and structural karyotypic abnormalities that we detected, were in agreement with published results. The detection of clonal karyotypic abnormalities was better after 3 d of culture without cytokine than in all other culture conditions. The higher percentage of patients at all stages of MM with an abnormal karyotype in our study (76 . 6%) than in previous ones (20% to 60%) is largely explained by the large number of mitoses analysed in six different culture conditions due to the use of a miniaturized karyotypic method.

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“…The measurement of absolute numbers of CD19 þ B cells, and the proportion of cells at each stage of differentiation, may be complicated in myeloma patients by the presence of varying proportions of neoplastic cells that are clonally related to the marrow plasma cells (Billadeau et al, 1992;Chiu et al, 1989). PCR studies using consensus Cm sequence primers have demonstrated the presence of cells with the same VDJ sequence found in the myeloma plasma cells linked to the Cm region (Bakkus et al, 1994;Corradini et al, 1993;Billadeau et al, 1993).…”

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B‐lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B‐cell progenitors and plasma cell precursors

et al. 1998

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Summary. The reduced levels of normal immunoglobulin in patients with myeloma may be due to suppression of normal B-cell differentiation. However, reports on the numbers of B cells vary, with some finding decreases consistent with immunoparesis, and others reporting expansions of phenotypically aberrant cells. We have therefore assessed the phenotype and levels of B lymphocytes in patients at presentation (n ¼ 23), in plateau or complete remission (PB n ¼ 42, BM n ¼ 18), and in relapse (PB n ¼ 17, BM n ¼ 14), in comparison to normal individuals (n ¼ 10). Phenotypic analysis was performed using five-parameter flow cytometry, with CD14 used to exclude monocytes where necessary.We found no evidence of a phenotypically distinctive blood or marrow B-cell population in patients with myeloma, nor of an increase in the levels of any B-cell subset. Numbers of blood CD19 þ 38 þ normal plasma cell precursors were significantly reduced in presentation/relapse patients, but not in patients in plateau/remission. Total CD19 þ cells were significantly reduced only in patients with circulating myeloma cells, detected by IgH-PCR. In the marrow, CD19þ B cells expressing CD5, CD10, CD34, CD38, CD45 low and Syndecan-1 were significantly decreased at presentation/relapse, but not in patients in plateau/remission. The majority of these antigens are expressed by normal B-cell progenitors, indicating that myeloma also affects the early stages of B-cell development. The suppression of progenitor cells was not restricted to B-lymphoid differentiation, as total CD34 þ cells were also significantly reduced in the marrow of myeloma patients at presentation.These results indicate that, if neoplastic B cells are present in myeloma, they are low in number and have a phenotype similar to their normal counterparts. Furthermore, there is a reversible suppression of CD19 þ B lymphocytes that correlates inversely with disease stage, and specifically affects the early and late stages of normal B-cell differentiation.

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Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients

Cited by 164 publications

References 23 publications

Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia

Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia

Cytogenetic study of 30 patients with multiple myeloma: comparison of 3 and 6 day bone marrow cultures stimulated or not with cytokines by using a miniaturized karyotypic method

B‐lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B‐cell progenitors and plasma cell precursors

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