scholarly journals PDTM-39. CRACKING THE HISTONE CODE: REVEALING THERAPEUTIC EPIGENETIC TARGETS THROUGH HISTONE H3 TAIL ANALYSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi196-vi196
Author(s):  
Daphne Li ◽  
Tina Huang ◽  
Jeannie Camarillo ◽  
Jin Qi ◽  
Hannah Weiss ◽  
...  
Keyword(s):  
Cell Lines ◽  
Histone H3 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Tumor Formation ◽  
Wild Type ◽  
Pontine Glioma ◽  
Pediatric Glioma ◽  
Mutation Status ◽  
Histone Codes ◽  
The Impact

Abstract INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is a highly morbid pediatric cancer. Up to 80% harbor a Histone H3K27M mutation, which alters wild type Histone H3 protein post-translational modifications (PTMs) and genomic enrichment patterns to impact chromatin structure and transcription regulation. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment in DIPG, and demonstrated pre-clinical efficacy of bromodomain inhibition (JQ1). Here, we employ a novel proteomics platform, developed at our institution, to further elucidate the impact of H3K7M mutation on glioma histone codes and response to bromodomain inhibition. METHODS Epiproteomic analysis was performed on pediatric glioma cell lines (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3.3 and H3.1 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h. Histones were extracted from isolated nuclei, immunopurified, and analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq results (H3K27M, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same DIPG cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results. RESULTS Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Relative H3 PTM abundance were compared across cell lines by tumor location, H3 mutation status, and in response to treatment. Significant differential genomic enrichment H3K27M and H3.3 WT proteins, H3K27Me3 and H3K27Ac were observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes. CONCLUSIONS Histone H3 tail epiproteomic analysis reveals DIPG histone codes in situ, revealing the effects of bromodomain inhibition on the tumor epigenetic landscape and providing new insight to the mechanism of tumor formation and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and longitudinal monitoring of treatment response are therefore currently underway.

scholarly journals Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma

2020 ◽  
Author(s):  
Shejuan An ◽  
Jeannie Camarillo ◽  
Tina Huang ◽  
Daphne Li ◽  
Juliette Morris ◽  
...  
Keyword(s):  
Cell Lines ◽  
Radiation Treatment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Response To Treatment ◽  
Wild Type ◽  
Post Translational Modification ◽  
Pontine Glioma ◽  
Epigenetic Signatures ◽  
The Impact

Abstract Background: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles.Methods: We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n=12) and cell lines (n=7).Results: We found 29.2% and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Conclusion: Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.

scholarly journals Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Shejuan An ◽  
Jeannie M. Camarillo ◽  
Tina Yi-Ting Huang ◽  
Daphne Li ◽  
Juliette A. Morris ◽  
...  
Keyword(s):  
Cell Lines ◽  
Radiation Treatment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Response To Treatment ◽  
Wild Type ◽  
Post Translational Modification ◽  
Pontine Glioma ◽  
Epigenetic Signatures ◽  
The Impact

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles. Methods We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n = 12) and cell lines (n = 7). Results We found 29.2 and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Conclusion Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.

scholarly journals Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma

2020 ◽  
Author(s):  
Shejuan An ◽  
Jeannie Camarillo ◽  
Tina Huang ◽  
Daphne Li ◽  
Juliette Morris ◽  
...  
Keyword(s):  
Cell Lines ◽  
Radiation Treatment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Response To Treatment ◽  
Wild Type ◽  
Post Translational Modification ◽  
Pontine Glioma ◽  
Epigenetic Signatures ◽  
The Impact

Abstract Background: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles. Methods: We performed targeted mass spectroscopy on H3.3K27M mutant and wild-type tissues (n=12) and cell lines (n=7). Results: We found 29.2% and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in distinct PTMs were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16 amino acid residues. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors relative to wild-type. Further, H3.3K36me2 was the most abundant modification co-occurring on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro , including increased H3K9me3. BRDi with JQ1 resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro . Conclusion: Taken together, our findings provide insight into the effects of the H3K27M mutation on Histone modification states and response to treatment, and suggest H3K36me2 and H4K16ac in DIPG may represent unique tumor epigenetic signatures for targeted therapy.

scholarly journals Histone Tail Analysis Reveals H3K36me2 And H4K16ac As Epigenetic Signatures of Diffuse Intrinsic Pontine Glioma

2020 ◽  
Author(s):  
Shejuan An ◽  
Jeannie Camarillo ◽  
Tina Huang ◽  
Daphne Li ◽  
Juliette Morris ◽  
...  
Keyword(s):  
Cell Lines ◽  
Radiation Treatment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Response To Treatment ◽  
Wild Type ◽  
Post Translational Modification ◽  
Pontine Glioma ◽  
Epigenetic Signatures ◽  
The Impact

Abstract Background: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles.Methods: We performed targeted mass spectroscopy on H3.3K27M mutant and wild-type tissues (n=12) and cell lines (n=7).Results: We found 29.2% and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in distinct PTMs were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16 amino acid residues. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors relative to wild-type. Further, H3.3K36me2 was the most abundant modification co-occurring on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. BRDi with JQ1 resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Conclusion: Taken together, our findings provide insight into the effects of the H3K27M mutation on Histone modification states and response to treatment, and suggest H3K36me2 and H4K16ac in DIPG may represent unique tumor epigenetic signatures for targeted therapy.

scholarly journals DIPG-39. NOVEL PROTEOMIC ANALYSIS REVEALS EPIGENETIC THERAPEUTIC TARGETS IN PEDIATRIC GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii294
Author(s):  
Daphne Li ◽  
Tina Huang ◽  
Jeannie Camarillo ◽  
Andrea Piunti ◽  
Jin Qi ◽  
...  
Keyword(s):  
Treatment Response ◽  
Cell Lines ◽  
Histone H3 ◽  
Therapy Response ◽  
Post Translational Modifications ◽  
Pediatric Glioma ◽  
Epigenetic Signatures ◽  
Monitoring Treatment ◽  
The Impact ◽  
H3k27m Mutation

Abstract INTRODUCTION Diffuse midline glioma is a highly morbid pediatric cancer. Up to 80% harbor Histone H3K27M mutation, which alters Histone H3 post-translational modifications (PTMs) and genomic enrichment patterns, affecting chromatin structure and transcription. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment and pre-clinical efficacy of bromodomain inhibition (JQ1) in DMG. Here, we employ a novel proteomics approach developed at our institution to further elucidate the impact of H3K27M mutation on glioma epigenetic signatures and treatment response. METHODS Epiproteomic analysis was performed on pediatric glioma cells (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h, Histones extracted from isolated nuclei and immunopurified, then analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq (H3.3K27M, H3.3, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results. RESULTS Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Significant differential PTM abundance and genomic enrichment H3K27M, H3.3 WT, H3K27Me3 and H3K27Ac was observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes. CONCLUSIONS Histone H3 tail analysis reveals the effects of H3K27M mutation and bromodomain inhibition on the tumor epigenetic landscape, providing insight into mechanisms of tumorigenesis and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and monitoring treatment response are therefore underway.

scholarly journals DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN: A RETROSPECTIVE STUDY INVESTIGATING THE FEASIBILITY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii291-iii292
Author(s):  
Alexandre Perez ◽  
Janak Nathan ◽  
Moatasem El-Ayadi ◽  
Christian Korff ◽  
Marc Ansari ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Controlled Trial ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Inclusion Criteria ◽  
Pontine Glioma ◽  
Randomized Controlled ◽  
Small Patient Population ◽  
Small Patient ◽  
The Impact ◽  
Aggressive Clinical Behavior

Abstract PURPOSE Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate the feasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients. METHODS Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition to a KD ≥ 3 months). One additional case was identified by contact with experts. The minimal feasibility criteria were defined as the ability to use the KD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators. RESULTS Five patients (males, n=3; median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (one patient – identified and not included - was on KD < 3 months due to disease progression). Further feasibility analyses showed a duration of the KD of ≥ 3 months and less than 7 months (n=2), > 7 months and less than 1 year (n= 2), and two years (n=1), respectively. CONCLUSION These results – based on a small patient population – suggest that the KD appears to be a feasible treatment option for children with DIPG. The potential duration of the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage further studies on a larger scale; ideally assessing the impact of the KD in DIPG patients in a randomized controlled trial.

Ventricular size determination and management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma: an institutional experience

2021 ◽  
pp. 1-7
Author(s):  
Adriana Fonseca ◽  
Palma Solano ◽  
Vijay Ramaswamy ◽  
Uri Tabori ◽  
Annie Huang ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Univariate Analysis ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Survival Advantage ◽  
Ventricular Size ◽  
Pontine Glioma ◽  
Asymptomatic Patients ◽  
Institutional Experience ◽  
Csf Diversion ◽  
The Impact

OBJECTIVE There is no consensus on the optimal clinical management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma (DIPG). To date, the impact on survival in patients with ventriculomegaly and CSF diversion for hydrocephalus in this population remains to be elucidated. Herein, the authors describe their institutional experience. METHODS Patients diagnosed with DIPG and treated with up-front radiation therapy (RT) at The Hospital for Sick Children between 2000 and 2019 were identified. Images at diagnosis and progression were used to determine the frontal/occipital horn ratio (FOR) as a method to measure ventricular size. Patients with ventriculomegaly (FOR ≥ 0.36) were stratified according to the presence of symptoms and categorized as follows: 1) asymptomatic ventriculomegaly and 2) symptomatic hydrocephalus. For patients with ventriculomegaly who did not require CSF diversion, post-RT imaging was also evaluated to assess changes in the FOR after RT. Proportional hazards analyses were used to identify clinical and treatment factors correlated with survival. The Kaplan-Meier method was used to perform survival estimates, and the log-rank method was used to identify survival differences between groups. RESULTS Eighty-two patients met the inclusion criteria. At diagnosis, 28% (n = 23) of patients presented with ventriculomegaly, including 8 patients who had symptomatic hydrocephalus and underwent CSF diversion. A ventriculoperitoneal shunt was placed in the majority of patients (6/8). Fifteen asymptomatic patients were managed without CSF diversion. Six patients had resolution of ventriculomegaly after RT. Of 66 patients with imaging at the time of progression, 36 (55%) had ventriculomegaly, and 9 of them required CSF diversion. The presence of ventriculomegaly at diagnosis did not correlate with survival on univariate analysis. However, patients with symptomatic hydrocephalus at the time of progression who underwent CSF diversion had a survival advantage (p = 0.0340) when compared to patients with ventriculomegaly managed with conservative approaches. CONCLUSIONS Although ventriculomegaly can be present in up to 55% of patients with DIPG, the majority of patients present with asymptomatic ventriculomegaly and do not require surgical interventions. In some cases ventriculomegaly improved after medical management with steroids and RT. CSF diversion for hydrocephalus at the time of diagnosis does not impact survival. In contrast, our results suggest a survival advantage in patients who undergo CSF diversion for hydrocephalus at the time of progression, albeit that advantage is likely to be confounded by biological and individual patient factors. Further research in this area is needed to understand the best timing and type of interventions in this population.

scholarly journals MR imaging features of diffuse intrinsic pontine glioma and relationship to overall survival: report from the International DIPG Registry

2020 ◽  
Vol 22 (11) ◽  
pp. 1647-1657 ◽  
Author(s):  
James L Leach ◽  
James Roebker ◽  
Austin Schafer ◽  
Joshua Baugh ◽  
Brooklyn Chaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariable Analysis ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Imaging Features ◽  
Pontine Glioma ◽  
Distant Disease ◽  
Mutation Status ◽  
Mri Features ◽  
Multivariable Analyses ◽  
Prospective Trials

Abtract Background This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG Registry (IDIPGR). Methods Four hundred cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of 2 neuroradiologists; 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed. Results On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. On central review, 9.5% of patients were considered not to have DIPG. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis, chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers. Conclusions Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review, demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable), only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status, although numbers are small and evaluation exploratory.

Targeting the Human Double Minute (HDM)-2 p53 Ubiquitin Ligase as a Strategy Against Non-Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1374-1374
Author(s):  
Richard J. Jones ◽  
Dajun Yang ◽  
Nathalie Bruey-Sedano ◽  
Robert Z. Orlowski
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Human Umbilical Cord ◽  
Wild Type ◽  
Inhibition Of Proliferation ◽  
P53 Expression ◽  
Non Hodgkin Lymphoma ◽  
Drug Concentrations ◽  
Chemotherapy Agents ◽  
The Impact

Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One such attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest, and apoptosis mediated by caspases-3, 8 and 9. MI-63 induced accumulation and phosphorylation of p53 at serine 15 and 37, and also enhanced HDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). MI-63 also decreased the levels of the ribonucleotide reductase subunit R2, and caused a corresponding increase in the R2p53 subunit. MI-63 also decreased the levels of E2F. Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in apoptosis. Cells without p53 expression were less sensitive to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Primary human umbilical cord vein endothelial cell growth was also inhibited and cells failed to recover after extended exposure to MI-63, whereas primary PBMC’s were unaffected by MI-63. Combinations of MI-63 with the molecularly targeted chemotherapy agents bortezomib and rapamycin were synergistic, with mean CI values of 0.88 and 0.6 respectively. The conventional chemotherapy agents doxorubicin and cisplatin were less effective at inducing synergism, with mean CI values of 1.06 and 0.9 respectively. Pretreatment of cells with MI-63 followed by chemotherapy was antagonistic with all agents used, while treatment with a chemotherapeutic first followed by MI-63 was additive to synergistic, indicating a sequence-dependent interaction. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rationale for translation of such agents into the clinic.

Sign in / Sign up

Export Citation Format

Share Document