A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA

Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.

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A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA

Blood ◽

10.1182/blood.v79.1.213.213 ◽

1992 ◽

Vol 79 (1) ◽

pp. 213-222 ◽

Cited By ~ 79

Author(s):

PA Moalli ◽

S Pillay ◽

D Weiner ◽

R Leikin ◽

ST Rosen

Keyword(s):

Multiple Myeloma ◽

Glucocorticoid Receptors ◽

Genomic Sequence ◽

Binding Activity ◽

Therapeutic Effects ◽

Early Form ◽

Ru 486 ◽

Human Multiple Myeloma ◽

Glucocorticoid Receptor Mrna ◽

Allelic Variations

Abstract Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.

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The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines

Blood ◽

10.1182/blood.v86.7.2747.2747 ◽

1995 ◽

Vol 86 (7) ◽

pp. 2747-2753 ◽

Cited By ~ 20

Author(s):

M Pettersson ◽

C Sundstrom ◽

K Nilsson ◽

LG Larsson

Keyword(s):

Multiple Myeloma ◽

B Cells ◽

B Cell ◽

Cell Lines ◽

Myeloma Cell ◽

Binding Activity ◽

Multiple Myeloma Cell ◽

Dna Binding Activity ◽

Human Multiple Myeloma ◽

Expression And Activity

Abstract PU.1 is a hematopoietic transcription factor belonging to the Ets-family. It is identical to the Spi-1 oncogene, which is implicated in spleen focus-forming virus-induced murine erythroleukemias. PU.1 seems to be required for early development of multiple hematopoietic lineages, but its expression in mature cells is preferentially observed in cells of the B-cell-and monocyte/macrophage-differentiation lineage. It binds the so-called Pu box, an important tissue-specific regulatory DNA element present in a number of genes expressed in these cell lineages. We have analyzed the expression and activity of PU.1 during human B-cell development using a panel of B-cell lines representing different stages of maturation, from early precursors to differentiated plasma cells. PU.1 mRNA expression and PU.1 DNA binding activity, as measured by Northern blot analysis and electrophoretic mobility shift assay, respectively, were evident in cell lines representing pro-B, pre- B, and mature B cells. We could also show Pu box-dependent transactivation of a reporter gene in transient transfections in these cell lines. In contrast, in a number of multiple myeloma cell lines, representing differentiated, plasma cell-like B cells, PU.1 DNA binding activity, mRNA expression, and Pu box-dependent transactivation were absent or detectable at a very low level. In lymphoblastoid cell lines, which exemplify an intermediate stage of B-cell differentiation, a reduced expression and activity were observed. The findings in the human multiple myeloma cell lines represent the first examples of B cells with downregulated PU.1 expression and apparently contradict observations in the murine system in which PU.1 is expressed and active in plasmacytoma cell lines. At present, it is unclear whether the lack of PU.1 expression and activity in human multiple myeloma cell lines represents a malignancy-associated defect in these cells or exemplifies a normal developmental regulation in terminally differentiated B cells.

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Chk1 inhibition potently blocks STAT3 tyrosine705 phosphorylation, DNA binding activity, and activation of downstream targets in human multiple myeloma cells

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-21-0366 ◽

2021 ◽

pp. molcanres.MCR-21-0366-E.2021

Author(s):

Liang Zhou ◽

Xinyan Pei ◽

Yu Zhang ◽

Yanxia Ning ◽

Lin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Dna Binding ◽

Binding Activity ◽

Myeloma Cells ◽

Downstream Targets ◽

Dna Binding Activity ◽

Human Multiple Myeloma

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The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines

Blood ◽

10.1182/blood.v86.7.2747.bloodjournal8672747 ◽

1995 ◽

Vol 86 (7) ◽

pp. 2747-2753 ◽

Cited By ~ 2

Author(s):

M Pettersson ◽

C Sundstrom ◽

K Nilsson ◽

LG Larsson

Keyword(s):

Multiple Myeloma ◽

B Cells ◽

B Cell ◽

Cell Lines ◽

Myeloma Cell ◽

Binding Activity ◽

Multiple Myeloma Cell ◽

Dna Binding Activity ◽

Human Multiple Myeloma ◽

Expression And Activity

PU.1 is a hematopoietic transcription factor belonging to the Ets-family. It is identical to the Spi-1 oncogene, which is implicated in spleen focus-forming virus-induced murine erythroleukemias. PU.1 seems to be required for early development of multiple hematopoietic lineages, but its expression in mature cells is preferentially observed in cells of the B-cell-and monocyte/macrophage-differentiation lineage. It binds the so-called Pu box, an important tissue-specific regulatory DNA element present in a number of genes expressed in these cell lineages. We have analyzed the expression and activity of PU.1 during human B-cell development using a panel of B-cell lines representing different stages of maturation, from early precursors to differentiated plasma cells. PU.1 mRNA expression and PU.1 DNA binding activity, as measured by Northern blot analysis and electrophoretic mobility shift assay, respectively, were evident in cell lines representing pro-B, pre- B, and mature B cells. We could also show Pu box-dependent transactivation of a reporter gene in transient transfections in these cell lines. In contrast, in a number of multiple myeloma cell lines, representing differentiated, plasma cell-like B cells, PU.1 DNA binding activity, mRNA expression, and Pu box-dependent transactivation were absent or detectable at a very low level. In lymphoblastoid cell lines, which exemplify an intermediate stage of B-cell differentiation, a reduced expression and activity were observed. The findings in the human multiple myeloma cell lines represent the first examples of B cells with downregulated PU.1 expression and apparently contradict observations in the murine system in which PU.1 is expressed and active in plasmacytoma cell lines. At present, it is unclear whether the lack of PU.1 expression and activity in human multiple myeloma cell lines represents a malignancy-associated defect in these cells or exemplifies a normal developmental regulation in terminally differentiated B cells.

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Bone sialoprotein mRNA and protein expression in human multiple myeloma cell lines and patients

British Journal of Haematology ◽

10.1046/j.1365-2141.2000.02506.x ◽

2000 ◽

Vol 111 (4) ◽

pp. 1118-1121 ◽

Cited By ~ 5

Author(s):

A. Bellahcene ◽

I. Van Riet ◽

C. de Greef ◽

N. Antoine ◽

M. F. Young ◽

...

Keyword(s):

Multiple Myeloma ◽

Protein Expression ◽

Cell Lines ◽

Myeloma Cell ◽

Bone Sialoprotein ◽

Multiple Myeloma Cell ◽

Human Multiple Myeloma ◽

Mrna And Protein Expression

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PP455 Cost-effectiveness Of Ixazomib-Based Regimen Compared With Bortezomib-Based Regimen In Chinese Patients With Relapsed/Refractory Multiple Myeloma: A Retrospective Study

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462320001798 ◽

2020 ◽

Vol 36 (S1) ◽

pp. 36-37

Author(s):

Pei Wang ◽

Jing Li ◽

Yang Yang ◽

Peng Liu

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Staging System ◽

Chinese Patients ◽

Disease Stage ◽

Control Group ◽

Therapeutic Effects ◽

Lower Grade ◽

Refractory Multiple Myeloma ◽

Grade 3

IntroductionThe treatment of relapsed/refractory multiple myeloma (RRMM), a common hematological malignancy, remains a great challenge in China, partially due to the limited accessibility to novel agents and inadequate public health insurance coverage. Ixazomib, a novel oral proteasome inhibitor (PI), was approved by the China Food and Drug Administration (CFDA) for RRMM in 2018. While bortezomib, a traditional PI, is the recommended agent in the clinical guideline for MM. Here, we compared their costs and effectiveness.MethodsRRMM patients who has received an ixazomib-based regimen (at least 2 cycles) were analyzed. Using a propensity score matching method, we generated a control group of RRMM patients who received the bortezomib-based regimen. The criteria included the number of treatment lines, age, and the revised international staging system stage (R-ISS) which representing the disease stage for myeloma, and paired at a ratio of 1:2 (allowing one control to match multiples). The difference in hospitalization stay, grade 3/4 adverse events rates, overall response rate (ORR), mortality during treatment, and treatment costs was then compared.ResultsNineteen patients received ixazomib and twenty-seven that received bortezomib were included. The ixazomib-group demonstrated a shorter hospital stay (9 days versus 27 days, p < 0.001), lower grade 3–4 adverse events rates (42.1% versus 55.6%, p < 0.001), higher ORR (63.2% versus 48.1%, p = 0.228), and lower mortality rate during treatment (0% versus 7.4%, p = 0.169) than that of bortezomib-group. The ixazomib group had lower total costs (127,620CNY versus 156,424CNY [18,033USD versus 22,103USD], p > 0.05), lower drug costs (98,376CNY versus 103,307CNY [13,901USD versus 14,598USD], p > 0.05), and the lower costs of supportive treatment (5,507CNY versus 14,701 CNY [778USD versus 2,077USD], p < 0.001). Only in terms of self-funded costs, the bortezomib-based regimen was significantly lower (37,127CNY versus 11,521CNY [5,246USD versus 1,628USD], p < 0.001).ConclusionsCompared with the bortezomib-based regimen, the ixazomib-based regimen has better therapeutic effects on MM patients while saving costs. Hence, it may be preferable for use in the treatment of RRMM in China.

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