Potential therapeutic biomarkers in plasma cell myeloma: A flow cytometry study

Zheng, Wenli; Liu, Dingshen; Fan, Xiangshan; Powers, Linda; Goswami, Maitrayee; Hu, Ying; Lin, Pei; Medeiros, L. Jeffrey; Wang, Sa A.

doi:10.1002/cyto.b.21083

Cited by 25 publications

(25 citation statements)

References 26 publications

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“…10,35 Having demonstrated regulation of IRF4 by a CD30/NF-kB positive feedback loop in PTCL cell lines, we sought to determine whether IRF4 expression was associated with expression of p52 and CD30 in PTCL tissue samples. Immunohistochemical staining for both p52 and CD30 was significantly higher in IRF4-positive PTCLs compared with IRF4-negative PTCLs (Figures 5F-H).…”

Section: Identification Of a Novel Positive Feedback Loop Involving Cmentioning

confidence: 99%

“…10 Although IRF4 ChIP has identified some interaction of IRF4 with the TNFRSF8 promoter in myeloma cells, CD30 protein is expressed infrequently in multiple myeloma clinical samples and cell lines (supplemental Figure 7). 10,35 Having demonstrated regulation of IRF4 by a CD30/NF-kB positive feedback loop in PTCL cell lines, we sought to determine whether IRF4 expression was associated with expression of p52 and CD30 in PTCL tissue samples. Immunohistochemical staining for both p52 and CD30 was significantly higher in IRF4-positive PTCLs compared with IRF4-negative PTCLs (Figures 5F-H).…”

Section: Irf4 Is a Direct Transcriptional Target Of Nf-kb In Ptclmentioning

confidence: 99%

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The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

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Section: Identification Of a Novel Positive Feedback Loop Involving Cmentioning

confidence: 99%

Section: Irf4 Is a Direct Transcriptional Target Of Nf-kb In Ptclmentioning

confidence: 99%

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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“…In contrast with T-ALL, CD30 was expressed less frequently by lymphoblasts in B-ALL. CD30 expression by neoplasms derived from B-cell lineage varies greatly, from 100% in classical Hodgkin lymphoma, to approximately 15–20% in diffuse large B cell lymphoma not otherwise specified (DLBCL NOS)[16], to less than 5% in plasma cell neoplasms [13]. Due to a low frequency of expression, comparisons of CD30 expression with treatment status in B-ALL or cytogenetic alterations may not be meaningful.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry staining was consistently much weaker and focal in all cases examined. Since immunohistochemistry[12,13] was not an optimal method in measuring CD30 expression on blasts, we focused the current study using flow cytometry assay only.…”

Section: Introductionmentioning

confidence: 99%

CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis

Zheng¹,

Medeiros²,

Young³

et al. 2013

Leukemia & Lymphoma

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We assessed CD30 expression in patients with acute lymphoblastic leukemia (ALL) of either T-cell or B-cell lineage to examine potential benefit of anti-CD30-targeted therapy in this group of patients. Bone marrow specimens of 34 patients with T- and 44 with B-acute lymphoblastic leukemia (ALL) were assessed for CD30 expression by multicolor flow cytometry immunophenotypic analysis. Of these 78 patients, 75(96%) were adults and 63(81%) had refractory/relapse disease. Using an arbitrary 20% cutoff, 13/34 (38%) T-ALL and 6/44 (14%) BALL cases were considered to express CD30. In 5 T-ALL patients with sequential bone marrow tested, increased CD30 expression was observed during the course of high dose chemotherapy (p=0.025). Philadelphia chromosome/BCR-ABL1 fusion was positive in 14/44 B-ALL and 2/32 of T-ALL which showed no significant correlation with CD30 expression. In summary, we detected CD30 expression in approximately one third of T-ALL patients, and less frequently in B-ALL (p=0.017). In T-ALL, CD30 expression is upregulated during high dose chemotherapy. These data indicate that anti-CD30-targeted therapy may be a potential option for T-ALL patients with refractory/relapsed disease.

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“…CD11a, CD49e, CD45RA and CD45RO may be expressed on a sub-population of tumour cells, characterised by lower malignancy and is further reduced during disease progression [93]. In PCM, CD49d shows bright uniform expression, whilst expressions of CD44 and CD184 are more heterogeneous [94]. …”

Section: Minimal Residual Disease (Mrd)mentioning

confidence: 99%

Towards Stratified Medicine in Plasma Cell Myeloma

Egan¹,

Drain²,

Conway³

et al. 2016

IJMS

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Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient’s age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as β-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder.

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Potential therapeutic biomarkers in plasma cell myeloma: A flow cytometry study

Cited by 25 publications

References 26 publications

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis

Towards Stratified Medicine in Plasma Cell Myeloma

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