RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

Mill, Christopher; Fiskus, Warren; DiNardo, Courtney D.; Qian, Yimin; Raina, Kanak; Rajapakshe, Kimal; Perera, Dimuthu; Coarfa, Cristian; Kadia, Tapan M.; Khoury, Joseph D.; Saenz, Dyana T.; Saenz, David N.; Illendula, Anuradha; Takahashi, Koichi; Kornblau, Steven M.; Green, Michael R.; Futreal, Andrew; Bushweller, John H.; Crews, Craig M.; Bhalla, Kapil N.

doi:10.1182/blood.2018893982

Cited by 81 publications

(69 citation statements)

References 64 publications

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“…For example, recent preclinical studies have identified addition of RUNX1-mutated cells to residual RUNX1 activity, which could be exploited with the use of BET inhibitors for a synthetic lethal result. 148 Similarly, a number of in vitro drug screens in RUNX1-mutated AML have identified glucocorticoids, phosphatidylinositol 3-kinase inhibitors, and JAK inhibitors as selectively effective. 61,149 In colorectal cancer and lung cancer cells, downregulation of GATA2 expression was shown to be synthetic lethal for oncogenic RAS mutations.…”

Section: Current Treatment Approaches and Novel Therapeutic Opportunimentioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

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Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

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Section: Current Treatment Approaches and Novel Therapeutic Opportunimentioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

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“…The most represented (n = 3) compound in the top 10 DSigDB drugs associated with the Hoxa del signature, Anisomycin, was recently identified as an expression mimic of mutant RUNX-1 (mt-RUNX-1) knockdown with specific potency against cells from AML patients with germline or somatic mt-RUNX-1 [51]. This is of particular interest as wild type RUNX-1 is essential for the maintenance of MLL-AF9 leukemia [52].…”

Section: Discussionmentioning

confidence: 99%

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Kettyle

Lebert-Ghali

Grishagin

et al. 2019

Cancers

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High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.

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“…In 2016, a VHL-based PROTAC (ARV-771) that also used OTX015 as the BRD4 warhead was generated [ 86 ]. Later, ARV-825 and ARV-771 were tested widely and displayed potent in vitro and in vivo efficacies against AML [ 104 , 105 ], post-myeloproliferative neoplasm secondary AML [ 106 , 107 ], MM [ 108 ], mantle cell lymphoma (MCL) [ 8 ], and DLBCL [ 109 ].…”

Section: Protacs Against Hematologic Malignanciesmentioning

confidence: 99%

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

Khan

Huo

et al. 2020

J Hematol Oncol

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a substoichiometric manner), ability to target "undruggable" and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/ selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.

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RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

Cited by 81 publications

References 64 publications

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

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