Constitutive Function of the Ikaros Transcription Factor in Primary Leukemia Cells from Pediatric Newly Diagnosed High-Risk and Relapsed B-precursor ALL Patients

Abstract Understanding the genomic and epigenetic mechanisms of drug resistance in pediatric acute lymphoblastic leukemia (ALL) is critical for further improvements in treatment outcome. The role of transcriptomic response in conferring resistance to l-asparaginase (LASP) is poorly understood, beyond asparagine synthetase (ASNS). We defined reproducible LASP response genes in LASP resistant and sensitive ALL cell lines (n = 7) as well as primary leukemia samples from newly diagnosed patients. We identified 2219 response genes (absolute log 2FC > 1.5, FDR p-value <0.05) with ~16.5% being reproduced in more than one cell line. Defining target genes of the amino acid stress response related transcription factor ATF4 in ALL cell lines using ChIP-seq revealed 25% of genes that changed expression after LASP treatment were direct targets of the ATF4 transcription factor. A total of 17,117 significantly differentially bound ATF4 sites were identified (FDR p-value <0.01) and 97.8% of these sites displayed an increase in ATF4 binding following LASP treatment. SLC7A11 was found to be a response gene in cell lines and patient samples as well as a direct target of ATF4. SLC7A11 was also one of only 2.4% of response genes with basal level gene expression that also correlated with LASP ex vivo resistance in primary leukemia cells from 212 newly diagnosed children enrolled on St. Jude Total Therapy 16. Experiments using chemical inhibition of SLC7A11 with sulfasalazine, gene overexpression, and partial gene knockout recapitulated LASP resistance or sensitivity in ALL cell lines. These findings show the importance of assessing changes in gene expression following treatment with an antileukemic agent for its association with drug resistance and highlights that many response genes may not differ in their basal expression in drug resistant leukemia cells. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Mullighan: Amgen: Current equity holder in publicly-traded company; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Pfizer: Research Funding. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee. Evans: Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months.

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Multiple myeloma immunoglobulin λ translocations portend poor prognosis

10.1101/340877 ◽

2018 ◽

Cited By ~ 1

Author(s):

Benjamin G. Barwick ◽

Paola Neri ◽

Nizar J. Bahlis ◽

Ajay K. Nooka ◽

Jonathan L. Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Transcription Factor ◽

High Risk ◽

Poor Prognosis ◽

Plasma Cells ◽

Whole Genome ◽

Newly Diagnosed ◽

Myeloma Cells ◽

Current Therapies ◽

Standard Risk

AbstractMultiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed ‘high-risk’. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

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Quantitative analysis of diffusion-weighted imaging in high-risk patients and newly diagnosed breast cancer patients; a systematic review

International Journal of Medicine in Developing Countries ◽

10.24911/ijmdc.51-1538825110 ◽

2019 ◽

pp. 1

Author(s):

Basmah Altuwayjiri

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Quantitative Analysis ◽

High Risk ◽

Cancer Patients ◽

Diffusion Weighted Imaging ◽

Newly Diagnosed ◽

Breast Cancer Patients ◽

High Risk Patients ◽

Risk Patients

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Long-Term Follow-Up of the Gem2010 Trial of Bortezomib-Melphalan-Prednisone and Lenalidomide-Dexamethasone in Elderly, Newly Diagnosed Multiple Myeloma Patients: Impact of Age, High-Risk Cytogenetics and Minimal Residual Disease

SSRN Electronic Journal ◽

10.2139/ssrn.3220103 ◽

2018 ◽

Author(s):

María-Victoria Mateos ◽

Joaquín Martínez-López ◽

Miguel-Teodoro Hernández ◽

Enrique-M Ocio ◽

Laura Rosiñol ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Minimal Residual Disease ◽

Residual Disease ◽

Newly Diagnosed ◽

Long Term Follow Up ◽

Minimal Residual

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MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia

BMJ Open ◽

10.1136/bmjopen-2020-046225 ◽

2021 ◽

Vol 11 (3) ◽

pp. e046225

Author(s):

Sarah Brown ◽

Debbie Sherratt ◽

Samantha Hinsley ◽

Louise Flanagan ◽

Sadie Roberts ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Plasma Cell ◽

Phase Ii ◽

Whole Body ◽

Cell Leukaemia ◽

High Dose ◽

Newly Diagnosed ◽

Genetic Changes ◽

Novel Treatment

IntroductionMultiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and disseminationEthics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN16847817, May 2017; Pre-results.

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Oral Metronomic Maintenance Therapy Can Improve Survival in High-Risk Neuroblastoma Patients Not Treated with ASCT or Anti-GD2 Antibodies

Cancers ◽

10.3390/cancers13143494 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3494

Author(s):

Xiaofei Sun ◽

Zijun Zhen ◽

Ying Guo ◽

Yuanhong Gao ◽

Juan Wang ◽

...

Keyword(s):

High Risk ◽

Conventional Treatment ◽

Maintenance Treatment ◽

Antibody Therapy ◽

Aggressive Treatment ◽

Newly Diagnosed ◽

Event Free Survival ◽

Free Survival ◽

Stage 4 ◽

Risk Patients

Despite aggressive treatment, the prognosis of high-risk NB patients is still poor. This retrospective study investigated the benefits of metronomic maintenance treatment (MT) in high-risk NB patients without ASCT or GD2 antibody therapy. Patients aged ≤ 21 years with newly diagnosed high-risk NB were included. Patients with complete/very good partial remission (CR/VGPR/PR) to conventional treatment received, or not, oral metronomic MT for 1 year. Two hundred and seventeen high-risk NB patients were enrolled. One hundred and eighty-five (85%) had a CR/VGPR/PR to conventional treatment, of the patients with stage 4, 106 receiving and 61 not receiving oral metronomic MT, and the 3-year event-free survival (EFS) rate was 42.5 ± 5.1% and 29.6 ± 6%, respectively (p = 0.017), and overall survival (OS) rate was 71.1 ± 4.7% and 59.4 ± 6.4%, respectively (p = 0.022). A total of 117 high-risk patients with oral metronomic MT had EFS rate of 42.7 ± 4.8%. The toxicity of MT was mild. For high-risk NB patients without ASCT or anti-GD2 antibody therapy, stage 4, MYCN amplication and patients with stage 4 not receiving oral metronomic MT after CR/VGPR/PR were independent adverse prognostic factors. Oral metronomic MT can improve survival in high-risk NB patients in CR/VGPR/PR without ASCT or anti-GD2 antibodies therapy.

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