p16 INK4a andp15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance

Blood ◽  
2001 ◽  
Vol 98 (1) ◽  
pp. 244-246 ◽  
Author(s):  
Gaëlle Guillerm ◽  
Emmanuel Gyan ◽  
Darius Wolowiec ◽  
Thierry Facon ◽  
Hervé Avet-Loiseau ◽  
...  
Keyword(s):  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Disease Stage ◽  
Early Event ◽  
Cell Cycle Regulators ◽  
Gene Methylation ◽  
History Of ◽  
P16 Ink4a ◽  
Polymerase Chain ◽  
Undetermined Significance

Abstract p15INK4b and p16INK4a proteins are cell cycle regulators involved in the inhibition of G1 phase progression. High frequency of methylation of both genes has been reported in multiple myeloma (MM), but it remains to be determined how and when these alterations contribute to tumorigenesis. Monoclonal gammopathy of undetermined significance (MGUS) represents an early disease stage in a fraction of MMs. Plasma cells from 33 patients with MGUS and 33 patients with MM were isolated and analyzed forp15INK4b and p16INK4amethylation by methylation-specific polymerase chain reaction. Selective methylation was found in 19% forp16INK4a, 36% forp15INK4b, and 6.5% for both genes in MGUS, and frequencies were similar in MM suggesting that methylation of these genes is an early event, not associated with transition from MGUS to MM. p15INK4b andp16INK4a gene methylation might contribute to immortalization of plasma cells rather than malignant transformation in the natural history of MM.

scholarly journals Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 289-296 ◽  
Author(s):  
D Billadeau ◽  
B Van Ness ◽  
T Kimlinger ◽  
RA Kyle ◽  
TM Therneau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Median Percentage ◽  
Color Flow ◽  
Circulating Cells ◽  
Allele Specific ◽  
Polymerase Chain ◽  
Undetermined Significance

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).

scholarly journals Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 289-296 ◽  
Author(s):  
D Billadeau ◽  
B Van Ness ◽  
T Kimlinger ◽  
RA Kyle ◽  
TM Therneau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Median Percentage ◽  
Color Flow ◽  
Circulating Cells ◽  
Allele Specific ◽  
Polymerase Chain ◽  
Undetermined Significance

Abstract The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).

The Chromosomal Pattern 14q-Translocation Plus 13q-Deletion Is Characteristic for Multiple Myeloma after a Preceding Monoclonal Gammopathy of Undetermined Significance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4873-4873
Author(s):  
Johannes Drach ◽  
Jutta Ackermann ◽  
Catrin Baldia ◽  
Hannes Kaufmann ◽  
Thomas Noesslinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Previous History ◽  
Low Frequency ◽  
P Value ◽  
History Of ◽  
Undetermined Significance

Abstract Multiple myeloma (MM) may be preceded by a monoclonal gammopathy of undetermined significance (MGUS), but it is at present unclear whether or not MM post-MGUS is biologically and clinically different from MM de-novo. To address this issue, we have performed a molecular cytogenetic analysis of 32 cases of MM post-MGUS (median time between recognition of MGUS and transition to MM, 7.6 years; range, 2.6 years to 19.5 years) and compared the findings with those of 256 patients with MM de-novo, in whom no previous history of MGUS had been documented. FISH studies of clonal plasma cells (cytoplasmic Ig positive) with probes for IgH translocations [t(14q32)], t(11;14)(q13;q32), t(4;14)(p16;q32), and deletion of 13q14 [del(13q14)] revealed results summarized in Table 1: Serial studies of MGUS plasma cells and MM post-MGUS plasma cells from 12 of these patients have thus far indicated that all chromosomal abnormalities observed at MM post-MGUS were already present in the MGUS plasma cells; most notably, there was one patient with t(4;14) plus del(13q) who had both abnormalities at the time of MGUS 94 months prior to transition to MM. Collectively, our data suggest that MM post-MGUS is characterized by a distinct chromosomal pattern, in particular a high frequency of t(14q32) plus del(13q14), frequent occurrence of a t(11;14), but low frequency of a t(4;14). We are currently studying the t(14q32) plus del(13q) chromosomal pattern in MGUS to investigate its potential value as a risk factor for transition from MGUS to MM. Table 1: FISH of MM post-MGUS versus MM de novo Abnormality MM post-MGUS MM de-novo P-value Any t(14q32) 24/32 (75%) 114/256 (44.5%) .05 t(11;14)(q13;q32) 9/32 (28.1%) 32/256 (12.5%) .05 t(4;14)(p16;q32) 2/32 (6.3%) 27/256 (10.6%) .37 del(13q14) 19/32 (59.4%) 102/256 (39.8%) .13 del(13q14) plus t(14q32) 18/19 (94.7%) 57/102 (55.8%) .11 del(13q14) plus t(11;14) 6/19 (31.6%) 9/102 (8.8%) .03

Interleukin‐6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance

1998 ◽  
Vol 101 (2) ◽  
pp. 287-295 ◽  
Author(s):  
Hamdi I. A. Sati ◽  
Jane F. Apperley ◽  
Mike Greaves ◽  
John Lawry ◽  
Roger Gooding ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Undetermined Significance

Comparison of Interleukin-1β Expression by In Situ Hybridization in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 300-305 ◽  
Author(s):  
Martha Q. Lacy ◽  
Kathleen A. Donovan ◽  
Julie K. Heimbach ◽  
Gregory J. Ahmann ◽  
John A. Lust
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Interleukin 1Β ◽  
Clinical Feature ◽  
Bone Lesions ◽  
Aberrant Expression ◽  
Undetermined Significance

Abstract We investigated whether interleukin-1β (IL-1β) is differentially expressed in plasma cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients because IL-1β appears to play a major role in the development of lytic bone lesions, the major clinical feature distinguishing MGUS from myeloma. In situ hybridization (ISH) for IL-1β was performed using bone marrow aspirates from 51 MM, 7 smoldering MM, 21 MGUS, and 5 normal control samples. Using the ISH technique IL-1β mRNA was detectable in the plasma cells from 49 of 51 patients with active myeloma and 7 of 7 patients with smoldering myeloma. In contrast, 5 of 21 patients with MGUS and 0 of 5 normal controls had detectable IL-1β message. Bone lesions were present in 40 of the 51 MM patients analyzed, and all 40 patients had IL-1β mRNA by ISH. These results show that greater than 95% of MM patients but less than 25% of MGUS patients are positive for IL-1β production. In the future, continued follow-up of IL-1β positive and negative MGUS patients should determine whether aberrant expression of plasma cell IL-1β is predictive of those MGUS patients that will eventually progress to active myeloma.

Prevalence of Light-Chain Monoclonal Gammopathy of Undetermined Significance (LC-MGUS) among Olmsted County, Minnesota Residents Aged 50 Years or Greater.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5060-5060
Author(s):  
S. Vincent Rajkumar ◽  
Robert Kyle ◽  
Matthew Plevak ◽  
Raynell Clark ◽  
Dirk Larson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
General Population ◽  
Natural History ◽  
Light Chain ◽  
Monoclonal Gammopathy ◽  
Olmsted County ◽  
Serum Samples ◽  
Geographic Population ◽  
History Of ◽  
Undetermined Significance

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that carries a 1% per year risk of progression to multiple myeloma (MM) or related malignancy. The prevalence and natural history of MGUS, in which by definition intact immunoglobulin heavy chain (IgH) is expressed, has been well described. However, up to 20% of myeloma (MM) is characterized by complete lack of IgH expression (Light-chain MM); the prevalence of a corresponding precursor entity, light chain MGUS (LC-MGUS) has not been determined. We report the first prevalence estimates of LC-MGUS in the general population from a large, well-defined geographic population using modern laboratory techniques. Methods: The cohort for this study was derived from one previously assembled by us to estimate the prevalence of MGUS (N Engl J Med2006;354:1362-9). The original cohort used to estimate the prevalence of MGUS consisted of 21,463 of the 28,038 enumerated residents aged 50 or over of Olmsted County Minnesota as of January 1, 1995. The sensitive serum free light chain (FLC) assay (The Binding Site Limited, Birmingham, U.K.) was performed on stored serum samples from these 21,463 persons. IgH expression was determined by immunofixation on all FLC results that had an abnormal kappa/lambda ratio (&lt;0.26 or &gt;1.65). LC-MGUS was defined as the presence of an abnormal FLC ratio and a negative immunofixation for IgH expression. Results: Adequate stored serum samples were available in 20,733 (97%) of the 21,463 persons. To date, the FLC assay has been performed and results were available for analysis on samples from 16,637 persons. An abnormal FLC ratio was observed in 572 persons. IgH expression was detected in 255 of these cases on immunofixation; these persons are considered as having MGUS, and were excluded from the estimation of LC-MGUS prevalence. This resulted in 317 persons out of 16,637 who had an abnormal FLC ratio without evidence of IgH expression, resulting in an estimated prevalence of LC- MGUS of 2%. Of the 317 cases of LC-MGUS identified in this study, 217 were kappa and 100 were lambda; in 35 cases the presence of the corresponding monoclonal light chain was apparent on immunofixation. The median age of the cohort of LC-MGUS was 62 years; males=151, females =166. The involved FLC level ranged from 0.118–270.0 mg/dL. The FLC ratio ranged from 0.014–0.253 (lambda) and 1.67–511.01 (kappa). So far, progression to multiple myeloma has occurred in 4 patients, a rate much higher than what is expected based on the prevalence of myeloma in the general population. Two additional patients have developed CLL. Conclusions: LC-MGUS is prevalent in 2% of the general population aged 50 years of age or older. The natural history of this disorder needs to be determined.

Obesity is Associated with a 2-Fold Elevated Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) Among African-American and Caucasian Women.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4876-4876
Author(s):  
Ola Landgren ◽  
Vincent Rajkumar ◽  
Ruth Pfeiffer ◽  
Robert Kyle ◽  
Jerry Katzmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
African Americans ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Pearson Correlation ◽  
Elevated Risk ◽  
Caucasian Women ◽  
Undetermined Significance

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Follow-up Care of Monoclonal Gammopathy of Undetermined Significance: A Guide for Primary Care Physicians

2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Hammad Z ◽  
◽  
Hernandez E ◽  
Tate S ◽  
◽  
...  
Keyword(s):  
Plasma Cell ◽  
Primary Care Physicians ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Organ Damage ◽  
M Protein ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
End Organ Damage ◽  
Undetermined Significance

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a condition in which M protein, an abnormal monoclonal immunoglobulin, is present in the blood at a nonmalignant level. Specifically, it is defined by: blood serum M protein concentration <3 g/dL (<30 g/L), <10% plasma cells in the bone marrow, and no evidence of end organ damage [1,2]. Evidence of end organ damage includes hypercalcemia, renal insufficiency, anemia, and bone lesions. These are indicative of MGUS progression and which can be attributed to the monoclonal plasma cell proliferative process [3]. MGUS occurs in 3% of the general population older than 50 years. Incidence increases with age and varies with sex with higher rates observered in males than females [1,4]. MGUS is the most common plasma cell disorder, with 60% of patients that present to the Mayo Clinic with a monoclonal gammopathy being diagnosed with MGUS [3]. While it is typically an asymptomatic condition, it is premalignant disorder to other monoclonal gammopathies. Multiple Myeloma (MM) is almost always preceded by MGUS and the majority of patients will have detectable levels of M protein for at least 5 years prior to MM diagnosis [5,6]. MGUS also precedes immunoglobulin light chain (AL) amyloidosis and Waldenstrom Macroglobulinemia (WM) and tends to progress to disorders at a fixed but unrelenting rate of 1% per year [4].

scholarly journals The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

2021 ◽  
Vol 16 (3) ◽  
pp. 26-32
Author(s):  
A. S. Khudovekova ◽  
Ya. A. Rudenko ◽  
A. E. Dorosevich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Bone Marrow Microenvironment ◽  
Genetic Mutations ◽  
Microbiome Composition ◽  
The Impact ◽  
Undetermined Significance

Multiple myeloma is a tumor of plasma cells, one of the most common malignant blood diseases. It is preceded by a stage called monoclonal gammopathy of undetermined significance, from which true multiple myeloma develops in only a small percentage of cases. It was assumed that this process is associated with the accumulation of genetic mutations, but in recent years there is increasing evidence that the bone marrow microenvironment plays a key role in progression and that it can become a target for therapy that prevents the myeloma development. The review considers the role of mesenchymal stem cells, immune system cells, endotheliocytes, fibroblasts, adipocytes, osteoclasts and osteoblasts in multiple myeloma progression, as well as the impact of the sympathetic nervous system and microbiome composition.

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