Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeted therapy for fusion-driven high-risk acute leukemia.

ABSTRACT: Despite continued progress in drug development for acute leukemias, outcomes for patients with some subtypes have not changed significantly in the last decade. Recurrent chromosomal translocations have long been recognized as driver events in leukemia, and many of these oncogenic fusions portend high-risk disease. Improved understanding of the molecular underpinnings of these fusions, coupled with novel chemistry approaches, now provide new opportunity for therapeutic inroads into the treatment of leukemia driven by these fusions.

SUBMITTER: Pikman Y

PROVIDER: S-EPMC6148448 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targeted therapy for fusion-driven high-risk acute leukemia.

Pikman Yana Y Stegmaier Kimberly K

Blood 20180726 12

Despite continued progress in drug development for acute leukemias, outcomes for patients with some subtypes have not changed significantly in the last decade. Recurrent chromosomal translocations have long been recognized as driver events in leukemia, and many of these oncogenic fusions portend high-risk disease. Improved understanding of the molecular underpinnings of these fusions, coupled with novel chemistry approaches, now provide new opportunity for therapeutic inroads into the treatment ...[more]

PMID: 30049809

Similar Datasets

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

Project description:BackgroundImproving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins.MethodsA screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, disulfiram (DSF), based on its efficient ablation of MLL-fusion proteins. The consequences of drug-induced MLL-fusion inhibition were confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and ChIP-qPCR and ChIP-seq analysis. All statistical tests were two-sided.ResultsDrug-induced inhibition of MLL-fusion proteins by DSF resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukaemia progression in vivo. Mechanistically, DSF abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukaemic programmes setup by the MLL-fusion protein.ConclusionDSF can directly inhibit MLL-fusion proteins and demonstrate antitumour activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly targets the initiating oncogenic MLL-fusion protein.

| S-EPMC9214753 | biostudies-literature

Non-toxic direct targeted therapy for MLL-fusion driven leukemias

Project description:Improving the poor prognosis of infant leukemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven pediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, Disulfiram, based on its efficient ablation of MLL fusion proteins. The consequences of drug-induced MLL-fusion inhibition was confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and CHIP-qPCR and CHIP-seq analysis. All statistical tests were two-sided. Drug-induced inhibition of MLL-fusion proteins by Disulfiram resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukemia progression in vivo. Mechanistically, Disulfiram abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukemic programs setup by the MLL-fusion protein. Disulfiram can directly inhibit MLL-fusion proteins and demonstrates antitumor activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly target the initiating oncogenic MLL-fusion protein.

2022-08-01 | GSE203203 | GEO

Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia.

Project description:Although cure rates for pediatric acute lymphoblastic leukemia (ALL) have now risen to more than 90%, subsets of patients with high-risk features continue to experience high rates of treatment failure and relapse. Recent work in minimal residual disease stratification and leukemia genomics have increased the ability to identify and classify these high-risk patients. In this review, we discuss this work to identify and classify patients with high-risk ALL. Novel therapeutics, which may have the potential to improve outcomes for these patients, are also discussed.

| S-EPMC7268159 | biostudies-literature

Advances in targeted therapy for acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) is a clonal malignancy characterized by genetic heterogeneity due to recurrent gene mutations. Treatment with cytotoxic chemotherapy has been the standard of care for more than half of a century. Although much progress has been made toward improving treatment related mortality rate in the past few decades, long term overall survival has stagnated. Exciting developments of gene mutation-targeted therapeutic agents are now changing the landscape in AML treatment. New agents offer more clinical options for patients and also confer a more promising outcome. Since Midostaurin, a FLT3 inhibitor, was first approved by US FDA in 2017 as the first gene mutation-targeted therapeutic agent, an array of new gene mutation-targeted agents are now available for AML treatment. In this review, we will summarize the recent advances in gene mutation-targeted therapies for patients with AML.

| S-EPMC7238648 | biostudies-literature

Is targeted therapy feasible in acute myelogenous leukemia?

Project description:The prognosis for patients with acute myeloid leukemia (AML) is determined to a large degree by the biology of the leukemic cell. In recent years, the identification and characterization of genetic aberrations has vastly improved our understanding of the pathogenesis of AML. In contrast, however, there has been a lack of clinically meaningful therapeutic advances. The same chemotherapeutic strategies have been applied to AML for several decades now, and while these regimens are effective in inducing remission, most patients relapse within months after initial treatment. Hence, there is an urgent need for novel therapies. We review herein a number of lines of laboratory and clinical trial data supporting the clinical value of targeted treatment approaches that will likely result in improved outcomes for patients with AML.

| S-EPMC4696009 | biostudies-literature

Molecular-Targeted Therapy of Pediatric Acute Myeloid Leukemia.

Project description:Acute myeloid leukemia (AML) accounts for approximately 15-20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML.

| S-EPMC9230975 | biostudies-literature

Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia.

Project description:Translocation t(12;21), resulting in the ETV6-RUNX1 (or TEL-AML1) fusion protein, is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia and is considered a first hit in leukemogenesis. A targeted therapy approach is not available for children with this subtype of leukemia. To identify the molecular mechanisms underlying ETV6-RUNX1-driven leukemia, we performed gene expression profiling of healthy hematopoietic progenitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces proliferation, survival and cellular homeostasis. In addition, Vps34, an important regulator of autophagy, was found to be induced by ETV6-RUNX1 and up-regulated in ETV6-RUNX1-positive leukemic patient cells. We show that induction of Vps34 was transcriptionally regulated by ETV6-RUNX1 and correlated with high levels of autophagy. Knockdown of Vps34 in ETV6-RUNX1-positive cell lines severely reduced proliferation and survival. Inhibition of autophagy by hydroxychloroquine, a well-tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1-positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1-positive leukemia samples to L asparaginase. These findings reveal a causal relationship between ETV6-RUNX1 and autophagy, and provide pre-clinical evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1-driven leukemia.

| S-EPMC6442983 | biostudies-literature

Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia.

Project description:Allogeneic hematopoietic cell transplantation (alloHCT) can cure previously treated high-risk chronic lymphocytic leukemia (CLL) patients if they are suitable for transplant through the graft-versus-leukemia effect. However, since the emergence of targeted therapies, the role of alloHCT for high-risk CLL is less clear. To address this question, we evaluated 108 high-risk CLL patients who underwent alloHCT from 2010 to 2018. Thirty patients from the period of 2013 to 2018 received targeted therapy prior to alloHCT. The median age for the targeted therapy cohort was 60 years (range, 30-71 years), and 20% and 73% had complete and partial remission, respectively: 76% had del(17p), 46.2% had 5 or more cytogenetic abnormalities, and 78.9% were IGHV unmutated. The median number of prior therapies was 4 (range, 1-9). With a median follow-up time of 36 months (range, 10-72 months), the 3-year overall (OS) and progression-free survival (PFS) were 87% and 69%, respectively. The 3-year cumulative incidence of nonrelapse mortality and relapse was 7% and 24%, respectively. For the control cohort of 78 patients who underwent alloHCT from 2010 to 2014 and received only chemoimmunotherapy prior to transplant, the 3-year OS and PFS were 69% and 58%, respectively. Patients treated with targeted therapy prior to alloHCT had a significantly higher number of circulating T and B cells and a lower ratio of CD4 regulatory T cells to CD4 conventional T cells early after transplant. In summary, despite multiple high-risk features, the clinical outcome of CLL patients who receive targeted therapy prior to transplant is excellent and alloHCT should be offered while the disease is under control.

| S-EPMC7479951 | biostudies-literature

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia.

Project description:NUP98-NSD1-positive acute myeloid leukemia (AML) is a poor prognostic subgroup that is frequently diagnosed in pediatric cytogenetically normal AML. NUP98-NSD1-positive AML often carries additional mutations in genes including FLT3, NRAS, WT1, and MYC. The purpose of our study was to characterize the cooperative potential of the fusion and its associated Neuroblastoma rat sarcoma (NRAS) mutation. By constitutively expressing NUP98-NSD1 and NRASG12D in a syngeneic mouse model and using a patient-derived xenograft (PDX) model from a NUP98-NSD1-positive AML patient, we evaluated the functional role of these genes and tested a novel siRNA formulation that inhibits the oncogenic driver NUP98-NSD1. NUP98-NSD1 transformed murine bone marrow (BM) cells in vitro and induced AML in vivo. While NRASG12D expression was insufficient to transform cells alone, co-expression of NUP98-NSD1 and NRASG12D enhanced the leukemogenicity of NUP98-NSD1. We developed a NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of the PDX mice. Our study demonstrates that mutated NRAS cooperates with NUP98-NSD1 and shows that direct targeting of the fusion can be exploited as a novel treatment strategy in NUP98-NSD1-positive AML patients.

| S-EPMC7600396 | biostudies-literature

Molecular landscape and targeted therapy of acute myeloid leukemia.

Project description:For decades, genetic aberrations including chromosome and molecular abnormalities are important diagnostic and prognostic factors in acute myeloid leukemia (AML). ATRA and imatinib have been successfully used in AML and chronic myelogenous leukemia, which proved that targeted therapy by identifying molecular lesions could improve leukemia outcomes. Recent advances in next generation sequencing have revealed molecular landscape of AML, presenting us with many molecular abnormalities. The individual prognostic information derived from a specific mutation could be modified by other molecular lesions. Therefore, the genomic complexity in AML poses a huge challenge to successful translation into more accurate risk stratification and targeted therapy. Herein, a summary of these mutations and targeted therapies are described. We focus on the prognostic information of recent identified molecular lesions and emerging targeted therapy.

| S-EPMC6225571 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data