scholarly journals Expression of the c-myc proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 180-191 ◽  
Author(s):  
R Greil ◽  
B Fasching ◽  
P Loidl ◽  
H Huber
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Proliferative Activity ◽  
Plasma Cells ◽  
Lymphocytic Leukemia ◽  
Myc Gene ◽  
Gene Transcripts

Abstract The c-myc gene plays a pivotal role in mediating the competence state for cell cycle transversion. This biologic role is in contradiction to reports of elevated expression of the gene in multiple myeloma, a tumor with restricted self-renewal capacity. To more clearly define the role of this gene in plasma cells of myeloma patients, c-myc messenger RNA (mRNA) and/or oncoprotein expression were semiquantitatively analyzed on the single cell level in 19 cases of multiple myeloma, among them 1 biclonal case and 1 case with coexistent chronic lymphocytic leukemia (CLL). Performing anti-sense/mRNA in situ hybridization, mature c-myc gene transcripts were detected in 92% (12 of 13) of cases and could definitely be attributed to the plasma cells by our study. The number of Ki 67-positive plasma cells actively passing the cell cycle was less than 1% and independent of c-myc gene expression. However, because the presence of the 152-c-MYC epitope was correlated to extent of marrow plasmacytosis (r = .64; P = .043) and content of plasmablasts (P = .09), the c-myc gene might serve a function different from proliferative activity, but also associated with tumor cell mass. In CLL cells (21 of 22 cases) and their benign counterparts, ie, bone marrow and peripheral blood lymphocytes, the anti-sense/c-myc mRNA hybridization signals remained below the threshold considered as cutpoint between negative and positive. The low amounts of c-myc transcripts were correlated to neither stage of disease (P = .52) nor lymphocyte counts (P = .24). Because the numbers of peripheral blood lymphoma cells were independent of tumor mass and of c-myc gene transcripts expressed, peripheral blood lymphocytosis might more likely reflect homing processes than proliferative activity in CLL.

scholarly journals Expression of the c-myc proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 180-191 ◽  
Author(s):  
R Greil ◽  
B Fasching ◽  
P Loidl ◽  
H Huber
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Proliferative Activity ◽  
Plasma Cells ◽  
Lymphocytic Leukemia ◽  
Myc Gene ◽  
Gene Transcripts

The c-myc gene plays a pivotal role in mediating the competence state for cell cycle transversion. This biologic role is in contradiction to reports of elevated expression of the gene in multiple myeloma, a tumor with restricted self-renewal capacity. To more clearly define the role of this gene in plasma cells of myeloma patients, c-myc messenger RNA (mRNA) and/or oncoprotein expression were semiquantitatively analyzed on the single cell level in 19 cases of multiple myeloma, among them 1 biclonal case and 1 case with coexistent chronic lymphocytic leukemia (CLL). Performing anti-sense/mRNA in situ hybridization, mature c-myc gene transcripts were detected in 92% (12 of 13) of cases and could definitely be attributed to the plasma cells by our study. The number of Ki 67-positive plasma cells actively passing the cell cycle was less than 1% and independent of c-myc gene expression. However, because the presence of the 152-c-MYC epitope was correlated to extent of marrow plasmacytosis (r = .64; P = .043) and content of plasmablasts (P = .09), the c-myc gene might serve a function different from proliferative activity, but also associated with tumor cell mass. In CLL cells (21 of 22 cases) and their benign counterparts, ie, bone marrow and peripheral blood lymphocytes, the anti-sense/c-myc mRNA hybridization signals remained below the threshold considered as cutpoint between negative and positive. The low amounts of c-myc transcripts were correlated to neither stage of disease (P = .52) nor lymphocyte counts (P = .24). Because the numbers of peripheral blood lymphoma cells were independent of tumor mass and of c-myc gene transcripts expressed, peripheral blood lymphocytosis might more likely reflect homing processes than proliferative activity in CLL.

scholarly journals Chronic lymphocytic leukemia (CLL) terminating in multiple myeloma: report of two cases

Blood ◽  
1978 ◽  
Vol 52 (3) ◽  
pp. 532-536 ◽  
Author(s):  
RH Kough ◽  
AZ Makary
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Medical Center ◽  
White Male ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
White Female ◽  
Pathologic Fractures

Abstract Two cases of multiple myeloma (MM) developed late in the course of chronic lymphocytic leukemia (CLL). An 81-yr-old white female developed, after 6 yr of CLL, IgAk MM with sheets of plasma cells abutting sheets of lymphocytes in the bone marrow, multiple pathologic fractures, and 0.26 g/24 free k light chains in the urine. A 74-yr-old white male developed, after 16 yr of CLL, k light chain MM with 20% plasma cells in the bone marrow, multiple panthologic fractures, and 3.7 g/24 hr free k light chains in the urine. In both cases the CLL had responded well to intermittent low-dose chlorambucil therapy, but the MM failed to respond to cyclic melphalanprednisone therapy. A review of 105 cases of CLL seen at the Geisinger Medical Center failed to turn up any other cases of MM developing during the course of CLL. The suggestion that there is an increased prevalence of MM in CLL is an attractive one because both diseases are B cell neoplasms and because of the increased frequency of asymptomatic monoclonal gammopathies in CLL found by others.

A Phase 1 Trial of SNS-032, a Potent and Specific CDK 2, 7 and 9 Inhibitor, in Chronic Lymphocytic Leukemia and Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3178-3178 ◽  
Author(s):  
William G. Wierda ◽  
R. Chen ◽  
William Plunkett ◽  
Steven Coutre ◽  
Ashraf Z. Badros ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Lymphocytic Leukemia ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Survival Factors

Abstract SNS-032, formerly BMS-387032, is a highly selective and potent inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. CDK2 and CDK7 are involved in cell cycle regulation. CDK7, along with CDK9, regulate RNA polymerase (Pol) II-dependent transcription. Temporary inhibition of RNA Pol II-dependent transcription by SNS-032 has significant effects on short half-life transcripts and proteins, particularly survival factors, cell cycle regulatory proteins, and cytokines that are critical for the survival of malignant B-cells in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). A phase 1 dose-escalation study in patients with MM and CLL is ongoing with separate dose escalations for each indication. The study is designed to evaluate safety, pharmacokinetics (PK) and preliminary evidence of activity of a loading dose (LD) followed by a 6 hour infusion of SNS-032 given weekly for 3 consecutive weeks of each 28-day cycle. Dose and schedule aim to maintain for 6 hours threshold plasma concentrations of 115 ng/mL (in vitro IC90) and higher. The study incorporates an exploratory analysis of potential pharmacodynamic (PD) biomarkers such as decreased phosphorylation of RNA Pol II C-terminal domain to demonstrate inhibition of CDK7 and CDK9, and decreased expression of survival factors to indicate transcriptional inhibition. Methods: Previously treated patients with advanced CLL or MM, measurable disease, and ECOG status 0–1 were eligible. Increasing doses of SNS-032 given as an LD followed by a 6 hr infusion were evaluated. The total starting dose was 15 mg/m2 comprised of a LD of 5 mg/m2 followed by 10 mg/m2 over 6 hr with dose escalation by modified Fibonacci. PD studies of target modulation were performed on peripheral blood mononuclear cells (PBMC) obtained pre- and post-dose. Direct target modulation or downstream effects of target inhibition were evaluated. Results: 35 patients have been treated to date, 18 MM patients and 17 CLL patients. Median age was 61 (range 45–82), with 13 females and 24 males. Median number of prior therapies was 5 (range: 1–11). MM patients have received total doses of 15 – 75 mg/m2. No drug-related dose limiting toxicities (DLTs) or objective responses have been reported thus far in MM. CLL patients have received total doses of 15 –100 mg/m2. No drug-related DLTs were observed through the 50 mg/m2 dose cohort. At 75 mg/m2, concentrations of SNS- 032 exceeded IC90 (mean maximum concentration during the 6 hr infusion was 261 ± 45 ng/mL). Evidence of biochemical tumor lysis syndrome (TLS) was observed in all CLL patients treated at this dose level. One patient experienced a DLT of vascular leak syndrome and failure to receive all 3 cycle 1 doses. One CLL patient has been treated thus far at 100 mg/m2. This patient experienced TLS with a DLT of elevated liver function enzymes for >48 hr and received only 2 of 3 doses in cycle 1. No objective responses have been observed. PD analyses showed evidence of decreased Mcl-1 or XIAP in several patients. Conclusions: The mechanism of action of SNS-032 supports testing this agent in B-cell malignancies such as MM and CLL. A pharmacologically-derived dose regimen that sustains IC90 SNS-032 concentrations or higher for 6 hr is being studied; target levels were achieved and exceeded in cohort 5 (75 mg/m2) for both MM and CLL. No DLTs or objective responses have been observed thus far in MM. AEs and DLTs related to mild to moderate TLS were observed in CLL patients at 75 mg/m2 and higher. No objective responses have been observed. Preliminary evidence of target-specific PD modulation has been demonstrated. Enrollment in this trial is continuing.

scholarly journals Expression of the c-myc protein is down-regulated at the terminal stages during in vitro differentiation of B-type chronic lymphocytic leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1025-1032 ◽  
Author(s):  
LG Larsson ◽  
M Schena ◽  
M Carlsson ◽  
J Sallstrom ◽  
K Nilsson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Terminal Differentiation ◽  
Antigen Expression ◽  
Lymphocytic Leukemia ◽  
Resting Cells ◽  
Ki 67 ◽  
Myc Oncogene ◽  
Myc Gene

Abstract The translocated c-myc oncogene in Burkitt's lymphoma (BL) and murine plasmacytoma (MPC) has been proposed to be expressed at a stage of differentiation at which the gene is normally silent, resulting in a continuous proliferation and an inhibited terminal differentiation. To determine whether c-myc is differently expressed at the various stages of the differentiation pathway, we used B-type chronic lymphocytic leukemia (B-CLL) cells, representing resting B lymphocytes, inducible to proliferation and/or differentiation in vitro. The c-myc protein, and Ig lambda-light chain and PCA-1 antigen as markers of B-cell maturation, were analyzed in single, morphologically defined cells by immunocytochemical double-staining. The proliferation of individual cells was determined by 3H-thymidine incorporation and by analysis of Ki-67 antigen expression. The results show that the level of c-myc expression correlates to the stage of differentiation and to the proliferative activity. Uninduced resting cells did not express c-myc. The c-myc protein was observed in the highest amount at the proliferative B-lymphoblast stage of maturation and was reduced in plasmablasts and undetectable in plasma cells. The results suggest that maturation of B cells into nonproliferative, terminally differentiated plasma cells is associated with a downregulated c-myc expression and thus support the view that the deregulated c-myc gene in BL and MPC is expressed at an inappropriate stage of maturation and thereby inhibits terminal differentiation.

Detection of Chromosomal Abnormalities in Chronic Lymphocytic Leukemia Increased by Interphase Fluorescence In Situ Hybridization in TPA-Stimulated Peripheral Blood Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4927-4927
Author(s):  
Anna Aventin ◽  
Jana Sanchez
Keyword(s):  
In Situ Hybridization ◽  
Chronic Lymphocytic Leukemia ◽  
Fluorescence In Situ Hybridization ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Cells ◽  
Trisomy 12

Abstract Chromosomal abnormalities, namely deletion 11q-,13q-, 17p- and trisomy 12, have prognostic significance for patients with chronic lymphocytic leukemia (CLL). Several studies have demonstrated that the interphase fluorescence in situ hybridization technique (I-FISH) in CLL identifies such genomic aberrations in a higher frequency than classical karyotyping, including stimulated cultures using B-cell specific mitogens. However, there appears to be no information in the literature comparing I-FISH on non-cultured and cultured cells in CLL. A total of 56 samples from 49 patients with CLL were studied using commercially available probes for chromosomes 11q22.3(ATM), 13q14(13S272), 17p13(p53) and 12 centromere(D12Z3). We compared the results obtained by I-FISH-PBMC and those by interphase fluorescence in situ hybridization on TPA-stimulated peripheral blood cells (I-FISH-TPA) used for conventional cytogenetics in order to evaluate the usefulness of I-FISH-TPA. The proportion of abnormal nuclei obtained with the I-FISH-TPA was higher than that found with I-FISH-PBMC (P<0.001). Consequently, 15 cases with a negative or borderline result by I-FISH-PBMC became positive by I-FISH-TPA for deletion 11q- (n=2), 13q- (n= 9) and trisomy 12 (n=4). In all but one of these, chromosomal abnormalities were reconfirmed by either metaphase-FISH or conventional G-banding. Disease detection thus increased from 51% with I-FISH-PBMC to 78% with I-FISH-TPA. Interestingly, all 15 cases which reached the diagnostic thresholds for deletion 11q-,13q- and trisomy 12 had a slight lymphocytosis. An absolute lymphocyte count <8.7×109/l was found to be the critical threshold (P=0.037) below which I-FISH-TPA should be performed rather than I-FISH-PBMC. We have shown that I-FISH-TPA can not only detect a higher proportion of abnormal interphase nuclei but can also identify abnormal CLL cases which may be overlooked by I-FISH-PBMC, especially those with low absolute lymphocyte counts. I-FISH-TPA is thus a reliable technique for clinical diagnostics in CLL.

scholarly journals Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2755-2763 ◽  
Author(s):  
Wee J. Chng ◽  
Roelandt F. Schop ◽  
Tammy Price-Troska ◽  
Irene Ghobrial ◽  
Neil Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Clone ◽  
Expression Profiles ◽  
Mapk Signaling ◽  
Lymphocytic Leukemia

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by the ability of the B-cell clone to differentiate into plasma cells. Although the clinical syndrome and the pathologic characteristics are well defined, little is known about its biology and controversy still exists regarding its cell of origin. In this gene-expression study, we compared the transcription profiles of WM with those of other malignant B cells including (chronic lymphocytic leukemia [CLL] and multiple myeloma [MM]) as well as normal cells (peripheral-blood B cells and bone marrow plasma cells). We found that WM has a homogenous gene expression regardless of 6q deletion status and clusters with CLL and normal B cells on unsupervised clustering with very similar expression profiles. Only a small gene set has expression profiles unique to WM compared to CLL and MM. The most significantly up-regulated gene is IL6 and the most significantly associated pathway for this set of genes is MAPK signaling. Thus, IL6 and its downstream signaling may be of biologic importance in WM. Further elucidation of the role of IL-6 in WM is warranted as this may offer a potential therapeutic avenue.

Double Hematological Malignancy: An Unusual Presentation in Three Cases

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5294-5294
Author(s):  
Rami Y. Haddad ◽  
Navneet Attri ◽  
Yaser Kawar
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
B Cell ◽  
Hematological Malignancies ◽  
Plasma Cells ◽  
Hematological Malignancy ◽  
Lymphocytic Leukemia ◽  
Refractory Anemia

Abstract The occurrence of more than one hematological malignancy in the same patient is an unusual pathologic condition and may pose a difficult challenge during decision to start various chemotherapy regimens. Cases of solid tumors of lung and gastrointestinal tract have been noted secondary to treatment of hematological malignancies but the occurrence of two hematological malignancies concomitantly is a rare presentation. We describe three cases of coexistent hematological malignancies at our institution. First case describes a 77 yo male with synchronously occurring B cell Non Hodgkin Lymphoma: marginal zone lymphoma (main bone marrow population); Chronic Lymphocytic leukemia (Fluorescent-in–situ hybridization test positive for trisomy 12) and a Monoclonal Beta, elevated IgM, elevated B2. BM evaluation revealed involvement by both processes. The patient has been started on Rituximab recently. The second case is an 85 yo male with findings with peripheral blood flow cytometry consistent with chronic lymphocytic leukemia of B-cell immunophenotype and lymph node biopsy consistent with Follicular Lymphoma. He was found to be BCL2 + on BM and had a normal Karyotype: 46, XY. He was treated with Rituximab ×8 cycles. A follow up PET scan showed partial response. Our third case was an 83 yo man with simultaneous presentation of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This patient had MDS (Refractory anemia with Ring sideroblasts RARS type) and smoldering Multiple myeloma (monoclonal plasma cells 10–15%) bone marrow infiltration which over a course of 3 years transformed into full blown Multiple Myeloma with bone marrow revealing 30–40% plasma cells and osteolytic lesions on skeletal survey. Cytogenetic were normal. He was treated with Lenalidomide (after failure of ESA) and became transfusion in dependent for one year (Hgb rose from baseline of 6–7 to 13 g/dL), after progression to active multiple myeloma he was treated with Thalidomide and Dexamthesone. He achieved a partial response on SPEP. Subsequently he was treated for MDS progression with Azacytidine for 5 cycles with minor hematological benefit (transfusion was less frequently), he recently succumbed to his disease, he was transfusion dependent and became acutely ill after an acute episode of diverticulitis. Patients with MM, MDS have been reported after chemotherapy but few cases documenting the coexistence of MDS and MM at diagnosis have been reported in the literature. Conclusion: In this report, we describe a three cases of double hematological clonal processes or malignancy, all diagnosed at same time, without preceding hematological disorder or chemotherapy, and all required treatment.

scholarly journals Chronic lymphocytic leukemia (CLL) terminating in multiple myeloma: report of two cases

Blood ◽  
1978 ◽  
Vol 52 (3) ◽  
pp. 532-536
Author(s):  
RH Kough ◽  
AZ Makary
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Medical Center ◽  
White Male ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
White Female ◽  
Pathologic Fractures

Two cases of multiple myeloma (MM) developed late in the course of chronic lymphocytic leukemia (CLL). An 81-yr-old white female developed, after 6 yr of CLL, IgAk MM with sheets of plasma cells abutting sheets of lymphocytes in the bone marrow, multiple pathologic fractures, and 0.26 g/24 free k light chains in the urine. A 74-yr-old white male developed, after 16 yr of CLL, k light chain MM with 20% plasma cells in the bone marrow, multiple panthologic fractures, and 3.7 g/24 hr free k light chains in the urine. In both cases the CLL had responded well to intermittent low-dose chlorambucil therapy, but the MM failed to respond to cyclic melphalanprednisone therapy. A review of 105 cases of CLL seen at the Geisinger Medical Center failed to turn up any other cases of MM developing during the course of CLL. The suggestion that there is an increased prevalence of MM in CLL is an attractive one because both diseases are B cell neoplasms and because of the increased frequency of asymptomatic monoclonal gammopathies in CLL found by others.

Sign in / Sign up

Export Citation Format

Share Document