scholarly journals Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6169
Author(s):  
Robyn A. Umans ◽  
Joelle Martin ◽  
Megan E. Harrigan ◽  
Dipan C. Patel ◽  
Lata Chaunsali ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Chromatin Immunoprecipitation ◽  
Glutamate Release ◽  
Transcriptional Regulator ◽  
Mutant P53 ◽  
Acid Transport ◽  
Wild Type ◽  
Gene Encoding ◽  
P53 Expression ◽  
Transcript Levels

Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1Met, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.

scholarly journals Expression of Wild-Type p53 by Curcumin, Alpinetin and Flavokawain B in Colorectal Cancer cells Expressing R273H Mutant p53

2020 ◽  
Vol 27 (2) ◽  
pp. 88-94
Author(s):  
I. Malami ◽  
A. Muhammad ◽  
I.B. Abubakar ◽  
A.M. Alhassan
Keyword(s):  
Bioactive Compounds ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Expression ◽  
Gene And Protein Expression ◽  
Colorectal Cancer Cells ◽  
Binding Core ◽  
Wild Type P53 ◽  
Dose Dependent

A mutation in p53 is frequently reported in nearly 50% of all of human cancers arising from DNA-binding core domain of p53. DNA-contact mutant R273H rendered p53 at dysfunctional state due to the substitution of single residue Arg273 for His273. Here, natural bioactive compounds curcumin, alpinetin and flavokawain B were investigated for possible stabilisation of wild-type p53 expression in vitro using HT-29 cells harbouring R273H rendered p53. Accordingly, all the bioactive compounds were able to induce the expression of wild-type p53 both at the levels of gene and protein expression. A dose-dependent induction of p53 was evident at 12.5, 25 and 50 μM concentration. The present study has shown that the bioactive compounds may have restored the wild-type p53 functional activity in tumour cells expressing R273H mutant p53. Keywords: Curcumin, Alpinetin, Flavokawain B, p53, R273H

An accelerated senescence response to radiation in wild-type p53 glioblastoma multiforme cells

2006 ◽  
Vol 105 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Quincy A. Quick ◽  
David A. Gewirtz
Keyword(s):  
Glioblastoma Multiforme ◽  
Growth Arrest ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Viable Cell Number ◽  
Mutant P53 ◽  
Wild Type ◽  
Fractionated Radiotherapy ◽  
Accelerated Senescence ◽  
Wild Type P53 ◽  
U87 Cells

Object Radiotherapy is one of the few treatment options available for glioblastoma multiforme (GBM); however, the basis for its overall ineffectiveness in GBM is not fully understood. The present study was designed to explore the nature of the response to ionizing radiation in GBM cells to gain insight into the basis for the general failure of radiotherapy in the treatment of this disease. Methods The response to fractionated radiotherapy was examined in GBM cell lines with differing p53 status. A viable cell number was determined during an 8-day period; accelerated senescence was based on β-galactosidase staining and cell morphology; apoptosis was evaluated by the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay and fluorescence-activated cell-sorter analysis, whereas the expression of cell-cycle regulatory proteins was monitored by Western blot analysis. Based on clonogenic survival, the wild-type p53 U87 cells and mutant p53 T98 cells demonstrated essentially identical sensitivity to fractionated radiotherapy; however, neither cell line underwent apoptosis, and the primary response to irradiation was growth arrest. The wild-type p53 GBM cells showed clear evidence of accelerated senescence in response to irradiation. In contrast, senescence was not evident in mutant p53 GBM cells or GBM cells in which p53 function was abrogated by the viral E6 protein. The T98 (mutant p53) cells demonstrated a relatively robust proliferative recovery whereas both the rate and extent of recovery were attenuated in the wild-type p53 U87 cells. Conclusions Both accelerated senescence and conventional growth arrest are likely to represent alternative responses to apoptosis in irradiated GBM cells.

High p53 Protein Expression LEVEL Independent Of Mutational Status Is An Adverse Prognostic Factor For Survival In ACUTE Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1330-1330
Author(s):  
Alfonso Quintas-Cardama ◽  
Sean M. Post ◽  
Kensuke Kojima ◽  
Yi Hua Qiu ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
P53 Pathway ◽  
P53 Expression ◽  
Mutational Status ◽  
Wild Type P53 ◽  
Acute Myeloid

Abstract Background The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML), particularly in cases with high-risk cytogenetics. It has been shown that p53 stabilization, which frequently occurs when the protein is mutated, can compromise its function. We have shown that p53 stabilization, regardless of the presence of mutations, suggesting alterations of other components in the p53 pathway. Methodology p53 expression was determined using high-throughput reverse phase protein array (RPPA) technology in 719 samples from 511 pts. Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1:2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status of p53 alleles was assessed by Sanger sequencing of exons 5 through 9. Expression of components of the p53 pathway was determined using standard immunohistochemical techniques. Nutlin-3a was used in in vitro culture experiments. Results Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). p53 expression correlated directly with CD34 (p=0.001) and inversely correlated with WBC (p=0.007), PB and BM blast burden (p=0.0001), and survival (p=0.01). High p53 (p53high) expression was more associated with unfavorable cytogenetics, particularly -5 (p=0.00001). p53high resulted in lower complete remission (CR) rates (51% vs 56%; p=??), higher relapsed rates (82% vs 62%; p=??), and shorter median overall survival (OS; 29.8 vs. 51 wks, p=0.009) compared to p53low pts. Most cases with p53high had unfavorable cytogenetics. We next correlated p53 stabilization with the presence of p53 mutations in 68 pts. p53 mutations were detected in 20/54 (37%) p53high pts and in 0/14 (0%) pts with p53low. p53high, either in the presence (29 wks) or in the absence (24 wks) of p53 mutations (p=1.0), was associated with significantly shorter OS compared with p53low pts (56 wks; p=0.05). Multivariate analysis revealed p53 expression to be an independent risk factor for survival in AML (p=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), BAD (p=0.0001), cleaved PARP (p=0.002), and cleaved PARP (p=0.01), and negatively with p21 (p=0.01), and MDM2 (p=0.001).Given the similar OS in p53high pts carrying mutant or wild-type p53, we scored the immunohistochemical expression of MDM2, MDM4, and p21 in 30 p53high pts (9 p53 mutated, 21 wild-type p53). Overexpression of MDM2 was observed in 44% vs 48% pts with mutant vs wild-type p53, respectively, whereas rates were 67% vs 62% for MDM4, and 0% vs 19% for p21, for each respective genotype. Overall, of the 21 p53high pts carrying wild-type p53, 15 (71%) had overexpression of MDM2 and/or MDM4, whereas 81% had no p21 expression, indicating deficient activation of the p53 pathway similar to those cases carrying mutant p53. We are currently assessing response to nutlin-3a therapy in 24 primary AML samples (4 mutant p53, 20 wild-type p53). Results showing the impact of p53 mutation and/or stabilization, and expression levels of MDM2, MDM4, and p21 on nutlin-3a therapy will be presented. Conclusions p53 stabilization (p53high) is a powerful predictive and prognostic factor in AML, which is independent of the presence of mutant p53 alleles. Poor outcomes in pts with p53high lacking p53 mutations are very frequently associated with overexpression of negative regulators of p53 such as MDM2 and/or MDM4 and p21 downregulation, indicating a functionally altered p53 pathway. These findings may have implications for therapies targeting the MDM2/p53 axis in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Oncogene ◽  
2021 ◽  
Author(s):  
Jennifer J. McCann ◽  
Irina A. Vasilevskaya ◽  
Christopher McNair ◽  
Peter Gallagher ◽  
Neermala Poudel Neupane ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Dna Binding ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Expression ◽  
Transcriptional Profiles ◽  
Cancer Types ◽  
Context Dependent ◽  
Wild Type P53

AbstractThe tumor suppressor gene TP53 is the most frequently mutated gene in numerous cancer types, including prostate cancer (PCa). Specifically, missense mutations in TP53 are selectively enriched in PCa, and cluster to particular “hot spots” in the p53 DNA binding domain with mutation at the R273 residue occurring most frequently. While this residue is similarly mutated to R273C-p53 or R273H-p53 in all cancer types examined, in PCa selective enrichment of R273C-p53 is observed. Importantly, examination of clinical datasets indicated that TP53 heterozygosity can either be maintained or loss of heterozygosity (LOH) occurs. Thus, to mimic tumor-associated mutant p53, R273C-p53 and R273H-p53 isogenic PCa models were developed in the presence or absence of wild-type p53. In the absence of wild-type p53, both R273C-p53 and R273H-p53 exhibited similar loss of DNA binding, transcriptional profiles, and loss of canonical tumor suppressor functions associated with wild-type p53. In the presence of wild-type p53 expression, both R273C-p53 and R273H-p53 supported canonical p53 target gene expression yet elicited distinct cistromic and transcriptional profiles when compared to each other. Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.

scholarly journals Targeting Aggregation of Wilde-Type p53 and Mutant p53 with ReACp53 As a Novel Therapeutic Concept for AML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3944-3944 ◽  
Author(s):  
Jianfang Zeng ◽  
Alice Soragni ◽  
Jo Ishizawa ◽  
Vivian Ruvolo ◽  
Christopher B. Benton ◽  
...  
Keyword(s):  
Cell Lines ◽  
Term Treatment ◽  
Mutant P53 ◽  
Amyloid Aggregation ◽  
Wild Type ◽  
Short Term ◽  
Short Term Treatment ◽  
P53 Expression ◽  
Hematopoietic Malignancies ◽  
Wild Type P53

Abstract Background: The tumor suppressor p53 is a master regulator of apoptosis, autophagy, cell cycle, and senescence. It is inactivated via mutation in approximately 50% of solid tumors, but only in 15% of hematopoietic malignancies including acute myeloid leukemia (AML). A recently proposed mechanism has linked loss of p53 function with its amyloid aggregation. Conceptually, certain p53 mutations can favor partial unfolding of the protein and expose a natively buried aggregation-prone segment. This can result in amyloidogenic aggregation and prevent p53 transcriptional activity and anti-tumor functions. The cell-permeable peptide ReACp53, has been recently developed to block p53 aggregation and restore its transcriptional function in the nucleus as well as its ubiquitination by MDM2. ReACp53 showed significant cytotoxicity in ovarian cancer but no toxicity to normal hematopoietic cells in animal experiment. We sought to determine the anti-tumor activity of ReACp53 in hematopoietic malignancies. Results: We examined the p53 status in 23 malignant hematopoietic cell lines by PCR, Sanger sequencing, and immunoblotting. Two cell lines were null for p53 expression, one harbored frame shift mutations, 11 cell lines expressed various missense p53 mutations, one cell line had an in frame deletion of p53, and eight cell lines expressed wild-type p53. Additionally, immunofluorescence staining (IF) with the conformation-specific PAb240 antibody revealed high levels of cytoplasmic, partially unfolded p53 in the cells expressing mutant p53. In p53 wild-type cells, p53 protein was mainly localized in the nucleus and was negative for PAb240. The p53 null and frame shift-mutant cells showed no p53 expression. All the cells were treated short-term with various concentrations of ReACp53, or a scrambled peptide, and assessed for apoptosis by flow cytometry. We found that ReACp53 was cytotoxic not only to the p53-mutant cells, but also to the wild-type p53 lines. In fact, all p53 wild type AML cell lines were highly sensitive. The p53 negative cell lines were seemingly resistant to short-term exposure to ReACp53. DeltaNp73, an isoform of p73 that antagonizes p53 and TAp73, is expressed in most AML cells and also has a similar aggregation-prone segment. We examined the levels of DeltaNp73 and total p73 in 12 AML cell lines by PCR, immunoblotting, and IF. Both proteins were overexpressed in all five wild-type p53 cell lines, and DeltaNp73 was predominately localized in the cytoplasm of these cells. After short-term treatment with ReACp53, DeltaNp73 expression and localization didn't change in wild type p53 AML cells. Over-expressing DeltaNp73 in HEK293T cells enhanced their level of Thioflavin T staining indicating amyloid aggregation of the protein. Compared to controls, the DeltaNp73 overexpressing HEK293T cells were more prone to apoptosis following ReACp53 treatment. Absent of transactivation domain, DeltaNp73 is not expected to be restored to function like TAp73. Mutant p53 is known to cross-aggregate p73 and p63 because of their highly similar aggregation-prone segments, therefore, we hypothesize that DeltaNp73 cross-aggregated p53 and p73 and ReACp53 inhibited the aggregation as to restore p53 and TAp73 function and exposure to MDM2. We chose two wild-type p53 AML cell lines, OCI-AML3 and MOLM-14, which express MDM2 and are sensitive to the MDM2 inhibitor DS3032b. After short-term treatment with ReACp53, p53 and p73 (also a MDM2 target) expression decreased significantly in both cells. We tested the anti-leukemia efficacy of the DS3032b and ReACp53 combinatorial treatment in these cells and found that DS3032b synergized with ReACp53 to efficiently kill the cells compared to the cytotoxic activity of DS3032b or ReACp53 treatment alone. Conclusions: We demonstrate a new mechanism of DeltaNp73 inhibition of wild-type p53 and TAp73 mediated by induction of amyloid aggregation. ReACp53 showed apoptogenic efficacy in malignant hematopoietic cells, both in cells expressing wild-type p53 as well as mutant p53. In the wild-type AML cells where p73 and DeltaNp73 were overexpressed, sensitivity to ReACp53 increased. ReACp53 also exhibited synergistic activity when combined with the MDM2 inhibitor DS3032b in wild-type p53 cells. Together, our data suggest a novel mechanism of p53 inactivation by amyloid formation, that can be corrected in acute myeloid leukemia carrying either wild-type or mutant p53. Disclosures No relevant conflicts of interest to declare.

scholarly journals aph(3′)-IIb, a Gene Encoding an Aminoglycoside-Modifying Enzyme, Is under the Positive Control of Surrogate Regulator HpaA

2003 ◽  
Vol 47 (12) ◽  
pp. 3867-3876 ◽  
Author(s):  
Lin Zeng ◽  
Shouguang Jin
Keyword(s):  
Transcriptional Regulator ◽  
Positive Control ◽  
Cross Reactivity ◽  
Metabolic Enzyme ◽  
Wild Type ◽  
Environmental Isolates ◽  
Gene Encoding ◽  
Neomycin B ◽  
Hydroxyphenylacetic Acid ◽  
Insight Into

ABSTRACT Pseudomonas aeruginosa harbors a chromosomal aminoglycoside phosphotransferase gene, aph(3′)-IIb, which confers P. aeruginosa resistance to several important aminoglycoside antibiotics, including kanamycin A and B, neomycin B and C, butirosin, and seldomycin F5. The aph(3′)-IIb gene has been found to be regulated by an AraC-type transcriptional regulator (HpaA) encoded by a gene located upstream of the aph(3′)-IIb gene. In the presence of 4-hydroxyphenylacetic acid (4-HPA), HpaA activates the expression of aph(3′)-IIb as well as that of the hpa regulon which encodes metabolic enzymes for the utilization of 4-HPA. hpaA and aph(3′)-IIb form an operon, and in response to the presence of 4-HPA, the wild-type P. aeruginosa strain PAK (but not its hpaA mutant strain) displays increased resistance to neomycin. A survey of 39 clinical and 19 environmental isolates of P. aeruginosa demonstrated in all of them the presence of an hpaA-aph gene cluster, while 56 out of the 58 isolates are able to utilize the 4-HPA as a sole carbon source, suggesting a feature common to P. aeruginosa strains. Interestingly, a larger portion of clinical isolates than environmental isolates showed 4-HPA-induced resistance to neomycin. The aph(3′)-IIb gene product is likely to function as a metabolic enzyme which has a cross-reactivity with aminoglycosides. These findings provide new insight into the possible mechanism of P. aeruginosa antibiotic resistance.

scholarly journals Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Vinaya Phatak ◽  
Yannick von Grabowiecki ◽  
Justyna Janus ◽  
Leah Officer ◽  
Caron Behan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinases ◽  
Mutant P53 ◽  
Interacting Proteins ◽  
Wild Type ◽  
Glycoprotein P ◽  
P53 Expression ◽  
P Glycoprotein ◽  
Endosomal Recycling ◽  
Coupling Protein

AbstractTP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.

Novel targets and interaction partners of mutant p53 Gain-Of-Function

2016 ◽  
Vol 44 (2) ◽  
pp. 460-466 ◽  
Author(s):  
Lydia Aschauer ◽  
Patricia A.J. Muller
Keyword(s):  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Invasion And Metastasis ◽  
Hallmarks Of Cancer ◽  
P53 Expression ◽  
The Past ◽  
Interaction Partners ◽  
Novel Targets ◽  
Underlying Mechanisms

In many human cancers p53 expression is lost or a mutant p53 protein is expressed. Over the past 15 years it has become apparent that a large number of these mutant p53 proteins have lost wild type function, but more importantly have gained functions that promote tumorigenesis and drive chemo-resistance, invasion and metastasis. Many researchers have investigated the underlying mechanisms of these Gain-Of-Functions (GOFs) and it has become apparent that many of these functions are the result of mutant p53 hijacking other transcription factors. In this review, we summarize the latest research on p53 GOF and categorize these in light of the hallmarks of cancer as presented by Hannahan and Weinberg.

Developing Therapeutic Strategies for CLL with Mutant p53

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2476-2476
Author(s):  
Hun Ju Lee ◽  
Miguel Gallardo ◽  
Xiaorui Zhang ◽  
Huaxian Ma ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Selective Pressure ◽  
Chromosome 17 ◽  
Treatment Modalities ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
P53 Expression ◽  
Mutational Status ◽  
Cytotoxic Treatment ◽  
Therapeutic Responses

Abstract Chronic lymphocytic leukemia (CLL) is a clonal disease marked by genetic heterogeneity, often resulting in varied therapeutic responses. As a consequence of these genetic variations, cytogenetic analyses are routinely employed to select the most efficacious treatment strategies. One of the most critical genetic variants used for CLL risk-stratification is deletion of the short arm of chromosome 17 (17p-). The tumor suppressor TP53 maps to this region, and its loss correlates with dismal outcomes. While FISH analyses for 17p- are routinely performed, the mutational status of TP53 is typically unknown. The importance of p53 mutations in leukemic progression have recently become apparent, as clinical studies have identified subsets of CLL patients that harbor TP53 mutations without an accompanying 17p- (Zenz et. al., JCO 2010); while other studies have suggest that p53 mutations are present in leukemic clones that expand following cytotoxic treatment (Wong et. al., Nature 2015). Thus, it is critical that we identify frontline treatment modalities that do not directly place undo selective pressure on the p53 pathway in CLL patients harboring a single TP53 mutation. In recent clinical trials, the Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib, has been shown effective in improving progression free survival in patients with CLL regardless of 17p- status (O'Brien et. al., Lancet Oncology 2014). However, little is known regarding how p53 mutations impact therapeutic responses given their known dominant-negative and gain-of-function effects. To this end, we have utilized a preclinical in vivo mouse model of B-CLL (Eµ-TCL1) in the presence or absence of a TP53 hot-spot mutation (p53R172H, corresponding to p53R175H in humans) to study its impact on therapeutic response, survival, and dynamic loss of the remaining wild-type Trp53 allele during the natural course of B-CLL following ibrutinib-based therapy. Cohorts of Eµ-TCL1; p53R172H/+ and Eµ-TCL1; p53WT mice were treated with ibrutinib 25mg/kg/day by oral gavage starting at 8 months of age. Ibrutinib significantly extended survival in both the Eµ-TCL1; p53R172H/+ and Eµ-TCL1; p53WT cohorts (Fig. 1A) and resulted in a reduction in CD5+CD19+ cells (Fig. 1B). Together, these data indicate ibrutinib's therapeutic efficacy even in the presence of mutated p53. To investigate the molecular pathways altered by ibrutinib in both the wild type and p53 mutant setting, we performed RNA-Seq analyses using malignant B-cells from treated and untreated Eµ-TCL1; p53R172H and Eµ-TCL1; p53WT mice. Critically, these analyses revealed that ibrutinib did not impact genes or cellular programs governed by p53 (Fig. 1C). Furthermore, RNA and protein analyses of tumor samples revealed that ibrutinib was directly impacted the BTK-, PLC-, MAPK-, and ERK- pathways regardless of p53 mutational status. Perhaps most important, we did not observe a significant loss of heterozygosity of the remaining wild type Trp53 allele in the ibrutinib treated Eµ-TCL1; p53R172H/+ lymphomas compared to untreated Eµ-TCL1; p53R172H/+. Together, these results directly indicate that ibrutinib does not place undo selective pressure on the remaining wild type Trp53 allele (Fig. 1D) and demonstrates that ibrutinib based treatment modalities may be effective treatment regimens in CLL patients harboring mutant p53. Even though ibrutinib effectively improved overall survival compared to vehicle treated animals, these mice eventually succumbed to the disease. Thus, it will be critical to examine mechanisms of ibrutinib-resistance in the setting of Trp53 mutations. To this end, expression analysis of ibrutinib treated Eµ-TCL1; p53R172H/+ mice revealed an interesting increase in T-cell immune regulatory pathways compared to Eµ-TCL1; p53WT treated cohorts. Currently, we are exploring the mechanism by which mutant p53 expression, exposure to ibrutinib, and regulations of immune-checkpoint genes. Disclosures No relevant conflicts of interest to declare.

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