Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

McCalmont, Hannah; Li, Ka Leung; Jones, Luke; Toubia, John; Bray, Sarah C; Casolari, Débora A.; Mayoh, Chelsea; Samaraweera, Saumya E.; Lewis, Ian D.; Prinjha, Rab K.; Smithers, Nicholas; Wang, Shudong; Lock, Richard B.; D’Andrea, Richard J.

doi:10.1182/bloodadvances.2019000586

Cited by 22 publications

(23 citation statements)

References 25 publications

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“…80 Instead, a combinatorial approach of therapies targeted towards different pathways, and/or in addition to conventional cytotoxic chemotherapeutics is likely to prove an optimal approach. Inhibitors targeting HDAC, 102 BET, 103,104 and menin 81…”

Section: Dot1l Inhibitorsmentioning

confidence: 99%

“…Instead, a combinatorial approach of therapies targeted towards different pathways, and/or in addition to conventional cytotoxic chemotherapeutics is likely to prove an optimal approach. Inhibitors targeting HDAC, 102 BET, 103,104 and menin 81 are ideal combinatorial agents in acute leukemia, inducing synergistic targeted effects in leukemic cells with either additional targeted therapies or conventional chemotherapeutic agents such as dexamethasone or vincristine. It is not known whether MLLT10 r with different fusion partners respond differently to specific targeted therapies, or if specific inhibitors are effective only in certain disease phenotypes such as B‐ALL, T‐ALL, ETP‐ALL or AML.…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

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MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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Rearrangements of the MLLT10 gene occur in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), most commonly T-lineage ALL (T-ALL), in patients of all ages. MLLT10 rearranged (MLLT10r) acute leukemia presents a complex diagnostic and therapeutic challenge due to frequent presentation of immature or mixed phenotype, and a lack of consensus regarding optimal therapy. Cases of MLLT10r AML or TALL bearing immature phenotype are at high risk of poor outcome, but the underlying molecular mechanisms and sensitivity to targeted therapies remain poorly characterized. This review addresses the incidence and prognostic significance of MLLT10r in acute leukemia, and how the aberrant gene expression profile of this disease can inform potential targeted therapeutic strategies. Understanding the underlying genomics of MLLT10r acute leukemia, both clinically and molecularly, will improve prognostic stratification and accelerate the development of targeted therapeutic strategies, to improve patient outcomes.

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Section: Dot1l Inhibitorsmentioning

confidence: 99%

Section: Hdac Inhibitorsmentioning

confidence: 99%

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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“…In parallel, JQ1 (a potent inhibitor of BRD4) greatly reduces MYC expression and activity, jointly with a large set of its target genes [88]. Moreover, JQ1 has also been tested in patient-derived xenograft from ALL patients, confirming its ability to inhibit MYC expression [90]. BET proteins are involved in maintaining aberrantly altered chromatin states in ALL.…”

Section: B Lymphoblastic Leukemia With the T(v;11) Mll Rearrangementmentioning

confidence: 95%

MYC’s Fine Line Between B Cell Development and Malignancy

Barrios

Meler

Parra

2020

Cells

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The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not completely silenced until the B cell becomes fully differentiated into a plasma cell or a memory B cell. MYC has been described as a proto-oncogene that is closely involved in many cancers, including leukemia and lymphoma. Aberrant expression of MYC protein in these hematological malignancies results in an uncontrolled rate of proliferation and, thereby, a blockade of the differentiation process. MYC is not activated by mutations in the coding sequence, and, as reviewed here, its overexpression in leukemia and lymphoma is mainly caused by gene amplification, chromosomal translocations, and aberrant regulation of its transcription. This review provides a thorough overview of the role of MYC in the developmental steps of B cells, and of how it performs its essential function in an oncogenic context, highlighting the importance of appropriate MYC regulation circuitry.

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“…Recent strategies advocate inhibition of other epigenetic modifiers, such as the enhancer of zeste homolog 2 (EZH2) ( 162 ), lysine demethylase 1A (KDM1A or LDS1) ( 163 ) and DOT1-like histone lysine methyltransferase (DOT1L) ( 164 ). The MLL subset interacts with DOT1L and the bromodomain and extra-terminal (BET) family member, bromodomain-containing 4 (BRD4), leading to potent inhibition ( 165 , 166 ). The OTX015 BET inhibitor is currently being clinically investigated following a phase 1 study ( 167 ).…”

Section: Therapies In Developmentmentioning

confidence: 99%

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

et al. 2020

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Recent studies have provided several insights into acute myeloid leukemia. Studies based on molecular biology have identified eight functional mutations involved in leukemogenesis, including driver and passenger mutations. Insight into Leukemia stem cells (LSCs) and assessment of cell surface markers have enabled characterization of LSCs from hematopoietic stem and progenitor cells. Clonal evolution has been described as having an effect similar to that of microenvironment alterations. Such biological findings have enabled the development of new targeted drugs, including drug inhibitors and monoclonal antibodies with blockage functions. Some recently approved targeted drugs have resulted in new therapeutic strategies that enhance standard intensive chemotherapy regimens as well as supportive care regimens. Besides the progress made in adoptive immunotherapy, since allogenic hematopoietic stem cell transplantation enabled the development of new T-cell transfer therapies, such as chimeric antigen receptor T-cell and transgenic TCR T-cell engineering, new promising strategies that are investigated.

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Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

Abstract: Key Points Cyclin-dependent kinase 9 and bromodomain and extraterminal inhibitors are synergistic in MLL-rearranged leukemia. Multiple AML driver genes are downregulated by the combined therapy suggesting broad applicability for this subtype.

Cited by 22 publications

References 25 publications

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

MYC’s Fine Line Between B Cell Development and Malignancy

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

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