scholarly journals RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

2018 ◽  
Author(s):  
Nan Zhou ◽  
Alvaro Gutierrez Uzquiza ◽  
Xiang Yu Zheng ◽  
Dan Vogl ◽  
Alfred L. Garfall ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zinc Finger Protein ◽  
Myeloma Cell ◽  
Primary Tumors ◽  
Genetic Ablation ◽  
Finger Protein ◽  
Therapeutic Opportunity ◽  
Related Transcription Factor ◽  
Runx Proteins ◽  
Transcription Factor 1

AbstractIkaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

scholarly journals Multiple myeloma cell lines and primary tumors proteome: protein biosynthesis and Immune system as potential therapeutic targets

2015 ◽  
Vol 6 (11-12) ◽  
pp. 462-471 ◽  
Author(s):  
Rodrigo Carlini Fernando ◽  
Fabricio de Carvalho ◽  
Diego Robles Mazzotti ◽  
Adriane Feijó Evangelista ◽  
Walter Moisés Tobias Braga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Cell Lines ◽  
Protein Biosynthesis ◽  
Therapeutic Targets ◽  
Myeloma Cell ◽  
Primary Tumors ◽  
Multiple Myeloma Cell

scholarly journals ZNF845 expression associates with survival in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Microarray Data ◽  
Triple Negative ◽  
Zinc Finger Protein ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Finger Protein ◽  
Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of zinc finger protein 845, encoded by ZNF845 when comparing the primary tumors of triple negative breast cancer patients dead or alive. ZNF845 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

scholarly journals ZNF248 is a differentially expressed gene in brain metastatic human breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Zinc Finger Protein ◽  
Differentially Expressed Gene ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Primary Tumors ◽  
Finger Protein ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that zinc finger protein 248, encoded by ZNF248, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. ZNF248 mRNA was present at decreased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of ZNF248 in primary tumors was significantly correlated with patient overall survival. Modulation of ZNF248 expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain in humans with metastatic breast cancer.

scholarly journals Differential expression of MAZ in cancers of the breast.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
High Frequency ◽  
Zinc Finger Protein ◽  
Normal Breast ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Finger Protein ◽  
Female Breast ◽  
Microarray Datasets

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We identified significant differential expression of the MYC-associated zinc finger protein and transcription factor MAZ when comparing primary tumors of the breast to the tissue of origin, the normal breast. MAZ may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals ZNF226 is over-expressed in brain metastatic breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Microarray Data ◽  
Zinc Finger Protein ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Primary Tumors ◽  
Finger Protein ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that the zinc finger protein 226, encoded by ZNF226 was among the genes whose expression was most different in the brain metastases of patients with brain metastatic breast cancer as compared to primary tumors of the breast. ZNF226 may be relevant to processes underlying metastasis of primary tumor-derived cancer cells to the brain in humans with metastatic breast cancer.

scholarly journals ZNF234 expression associates with survival in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Zinc Finger Protein ◽  
Molecular Subtype ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Finger Protein ◽  
Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of zinc finger protein 234, encoded by ZNF234 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, ZNF234 expression was correlated with post-progression survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. ZNF234 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

GAMMA-RADIATION UPREGULATES MHC CLASS I/II AND ICAM-I MOLECULES IN MULTIPLE MYELOMA CELL LINES AND PRIMARY TUMORS

2006 ◽  
Vol 42 (3) ◽  
pp. 89 ◽  
Author(s):  
MAURIZIO CHIRIVA-INTERNATI ◽  
FABIO GRIZZI ◽  
JUSTIN PINKSTON ◽  
K. JOHN MORROW ◽  
NICHOLAS D'CUNHA ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Gamma Radiation ◽  
Mhc Class I ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Class I ◽  
Primary Tumors ◽  
Multiple Myeloma Cell

Gamma-radiation up-regulates MHC Class I/II and ICAM-I molecules in Multiple Myeloma cell lines and primary tumors

2006 ◽  
Author(s):  
Maurizio Chiriva-Internati ◽  
Fabio Grizzi ◽  
Justin Pinkston ◽  
K. John Morrow ◽  
Nicholas D'Cunha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Gamma Radiation ◽  
Mhc Class I ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Class I ◽  
Primary Tumors ◽  
Multiple Myeloma Cell

scholarly journals Loss of IRF4 Results in Multiple Myeloma Cell Apoptosis through the Transcriptional up-Regulation of the BH3-Only Proteins Bmf and BIM

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3103-3103
Author(s):  
Pasquale L. Fedele ◽  
Yang Liao ◽  
Jianan Gong ◽  
Mark van Delft ◽  
Michael S.Y. Low ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
Cell Lines ◽  
Transcriptional Repression ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Genetic Ablation ◽  
Apoptotic Proteins

The transcription factor IRF4 is essential for the survival of both normal plasma cells and the plasma cell malignancy multiple myeloma (MM). However the basis for this dependency remains uncertain, with the prevailing view that IRF4 loss in MM induces "death by a thousand cuts." Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 mediated deletion of IRF4 in three lenalidomide sensitive MM cells lines (MM1S, OPM2 and H929) and one resistant cell line (RPMI-8226). Loss of IRF4 resulted in marked loss of viability, irrespective of lenalidomide sensitivity, which was driven by two distinct mechanisms: 1) induction of apoptosis, which was rescued through prior deletion of apoptotic mediators BAX and BAK, and 2) proliferative arrest, which persisted despite rescue from apoptosis. RNA-sequencing following IRF4 inactivation identified a core group of 86 genes whose dysregulation was shared across all 4 MM cell lines. We identified 31 common down-regulated genes (IRF4 activated), including several with previously described roles in survival (such as KLF2, TNFRSF17/BCMA and MYB). Furthermore, MYC, a previously identified target of IRF4 known to play an important role in MM pathogenesis and survival, was down-regulated in 3 of the 4 cell lines. Most surprisingly, IRF4 inactivation resulted in 55 common up-regulated genes that included two BH3-only pro-apoptotic proteins, BMF and BCL2L11 (BIM). Up-regulation of BMF appeared more marked than BIM with an average fold change of 6.5x (range 2.7 - 10.3) vs 1.9x (range: 1.8 - 2.2) respectively. Remarkably, genetic ablation of BMF in the OPM2 cell line and BMF/BIM in the MM1S largely protected from the cell death observed following IRF4 inactivation, suggesting that IRF4 maintains MM survival through the transcriptional repression of BMF and BIM. Our results confirm the vital role of IRF4 for MM proliferation and survival, and shed further light into its critical downstream transcriptional targets. Most interestingly, we have demonstrated that the 'killer blow' appears to be the concerted effect of the BH3-only pro-apoptotic proteins BMF and BIM. Disclosures Huang: Genentech: Patents & Royalties: DCSH is an employee of the Walter and Eliza Hall Institute which receives milestone and royalty payments related to venetoclax.

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