Epigenetic regulators and their impact on therapy in acute myeloid leukemia

Pastore, Friederike; Levine, Ross L.

doi:10.3324/haematol.2015.140822

Cited by 41 publications

(35 citation statements)

References 154 publications

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“…Previous work has identified the differentiation state of AML cells as a primary source of epigenetic variation (21–23). This is consistent with the observation that certain key HSPC enhancers, such as the SE linked to CDK6, show strong variability across our AML cohort (Fig.…”

Section: Resultsmentioning

confidence: 99%

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

McKeown¹,

Corces

Eaton³

et al. 2017

Cancer Discovery

121

153

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We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of APL treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.

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Section: Resultsmentioning

confidence: 99%

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

McKeown¹,

Corces

Eaton³

et al. 2017

Cancer Discovery

121

153

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“…These investigations have the potential to reveal crosstalk networks between epigenetic modulators, such as PRMT5, and signaling pathways influenced by PRMT5 inhibition (such as ERK/STAT1), thereby opening the door to synergistic interactions of future drug combinations. Epigenetic modifiers are appealing targets for aGVHD not only because of the role epigenetics has in immune regulation but also because many epigenetic modifying agents are used as treatments against hematopoietic neoplasms (72,73). A variety of epigenetic modifiers are currently being evaluated as potential aGVHD therapeutics in phase I and phase II clinical trials, primarily as combinatorial therapies with other well-established aGVHD treatments (74,75).…”

Section: Discussionmentioning

confidence: 99%

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Snyder¹,

Zitzer²,

Gao³

et al. 2020

JCI Insight

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“…The hypomethylating agents (HMAs), azacitidine and decitabine, are nucleoside analogs that integrate into DNA and inhibit DNMTs [23]. Along with LDAC, they represent a reasonable treatment option for low blast count AML patients who are unfit for intensive induction chemotherapy with CRc rates around 20–30% [4].…”

Section: Epigenetic Modifiersmentioning

confidence: 99%

Emerging therapies for acute myeloid leukemia

2017

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Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.

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Epigenetic regulators and their impact on therapy in acute myeloid leukemia

Cited by 41 publications

References 154 publications

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Emerging therapies for acute myeloid leukemia

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