Novel inhibitors of the histone methyltransferase DOT1L show potent antileukemic activity in patient-derived xenografts

Perner, Florian; Gadrey, Jayant Y.; Xiong, Yijun; Hatton, Charlie; Eschle, Benjamin K.; Weiss, Andreas; Stauffer, Frédéric; Gaul, Christoph; Tiedt, Ralph; Perry, Jennifer A.; Armstrong, Scott A.; Krivtsov, Andrei V.

doi:10.1182/blood.2020006113

Cited by 33 publications

(36 citation statements)

References 17 publications

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“…Several studies have suggested that KMT2A-AF9 fusion leukemias are particularly sensitive to pharmacological inhibition of the Dot1L methyltransferase activity 44,45 . We hypothesize that elevated Dot1L signal at dprotein target sites might indicate sensitivity Dot1L inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia

Janssens

Babaeva

et al. 2020

Preprint

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Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the Mixed Lineage Leukemia-1 gene, which encodes the KMT2A lysine methyltransferase. The most common translocations produce in-frame fusions of KMT2A to trans-activation domains of chromatin regulatory proteins. Here we develop a strategy to map the genome-wide occupancy of oncogenic KMT2A fusion proteins in primary patient samples regardless of fusion partner. By modifying the versatile CUT&Tag method for full automation we identify common and tumor-specific patterns of aberrant chromatin regulation induced by different KMT2A fusion proteins. Integration of automated and single-cell CUT&Tag uncovers lineage heterogeneity within patient samples and provides an attractive avenue for future diagnostics.

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Section: Resultsmentioning

confidence: 99%

Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia

Janssens

Babaeva

et al. 2020

Preprint

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“…Preclinical studies have demonstrated clinical activity of oral small molecule Menin-MLL inhibitors in KMT2A -R cell line and murine models [ 52 , 53 ] and early phase clinical trials have recently been initiated in patients with R/R acute leukaemias. Enzymatic inhibitors of DOT1L, a histone 3 lysine 79 (K3K79) methyltransferase and essential downstream mediator of the KMT2A-R oncogenic program, is another promising approach [ 54 , 55 ].…”

Section: Targeting the Menin-mll1 Interaction In Kmt2a Rearranged Leukaemiamentioning

confidence: 99%

Targeted Therapy in Acute Lymphoblastic Leukaemia

Salvaris

Fedele

2021

JPM

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The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.

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“…New generations of orally available inhibitors with improved pharmacokinetics are also being developed, which will improve clinical utility and may increase responses to DOT1L-inhibition. 13 , 14 …”

Section: Targeting Mll-rearranged Amlmentioning

confidence: 99%