Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Tayari, Mina M.; Santos, Helena; Kwon, Deukwoo; Bradley, Terrence; Thomassen, Amber; Chen, Charles Jeng; Dinh, Yvonne; Perez, Aymee; Zelent, Arthur; Morey, Lluís; Cimmino, Luisa; Shiekhattar, Ramin; Swords, Ronan; Watts, Justin M.

doi:10.1158/1078-0432.ccr-20-4054

Cited by 26 publications

(14 citation statements)

References 49 publications

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“…Molecular markers associated with response were not identified and a global increase in H3K4me2 upon TCP was only observed in two patients (50). In nonresponders to TCP and ATRA combination therapy there was enrichment for expression of genes involved in mTOR signaling and for expression of higher basal histone deacetylase 2 (HDAC2) (51). Moreover, treatment of MLL-rearranged AML with the LSD1 inhibitor GSK-LSD1 caused global gains in chromatin accessibility, with a strong enrichment of PU.1 and C/EBPa at these open sites.…”

Section: Epigenetically-driven Drug Resistance In Amlmentioning

confidence: 99%

Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia

2021

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Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapy for many years to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions in the majority of patients, many face a relapse (adaptive resistance) or have refractory disease (primary resistance). Moreover, older patients are often unfit for cytotoxic-based treatment. AML relapse is due to the survival of therapy-resistant leukemia cells (minimal residual disease, MRD). Leukemia cells with stem cell features, named leukemic stem cells (LSCs), residing within MRD are thought to be at the origin of relapse initiation. It is increasingly recognized that leukemia “persisters” are caused by intra-leukemic heterogeneity and non-genetic factors leading to plasticity in therapy response. The BCL2 inhibitor venetoclax, combined with hypomethylating agents or low dose cytarabine, represents an important new therapy especially for older AML patients. However, often there is also a small population of AML cells refractory to venetoclax treatment. As AML MRD reflects the sum of therapy resistance mechanisms, the different faces of treatment “persisters” and LSCs might be exploited to reach an optimal therapy response and prevent the initiation of relapse. Here, we describe the different epigenetic, transcriptional, and metabolic states of therapy sensitive and resistant AML (stem) cell populations and LSCs, how these cell states are influenced by the microenvironment and affect treatment outcome of AML. Moreover, we discuss potential strategies to target dynamic treatment resistance and LSCs.

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Section: Epigenetically-driven Drug Resistance In Amlmentioning

confidence: 99%

Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia

2021

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“…As the first discovered histone demethylase, LSD1 has promoted the research progress of epigenetics. LSD1 is a key regulator of the proliferation, apoptosis, differentiation, invasion, metastasis, drug resistance, and cancer stemness and hence is a promising therapeutic target for cancers ( Feng Z. et al, 2016 ; Wang et al, 2016 ; Alsaqer et al, 2017 ; Cusan et al, 2018 ; Verigos et al, 2019 ; Tayari et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

Yang

Zang

et al. 2022

Front. Pharmacol.

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Epigenetics has emerged as a prime focus area in the field of cancer research. Lysine-specific demethylase 1A (LSD1), the first discovered histone demethylase, is mainly responsible for catalysing demethylation of histone 3 lysine 4 (H3K4) and H3K9 to activate or inhibit gene transcription. LSD1 is abnormally expressed in various cancers and participates in cancer proliferation, apoptosis, metastasis, invasion, drug resistance and other processes by interacting with regulatory factors. Therefore, it may serve as a potential therapeutic target for cancer. This review summarises the major oncogenic mechanisms mediated by LSD1 and provides a reference for developing novel and efficient anticancer strategies targeting LSD1.

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“…Its expression is directly regulated by PML/RARa and it coordinates with the fusion protein to maintain APL, in such a way that the PML/RARa-induced differentiation block can be relieved upon GFI1 knockdown [45]. Accordingly, LSD1 inhibition sensitizes AML cell lines to retinoic acid treatment through the blockage of LSD1:GFI1 interaction [46]. Finally, it is interesting to note that treatment of NB4 promyelocytic leukemia cells with LSD1 inhibitors leads to reduced association of the coiled-coil protein GSE1 with LSD1 [47,48], as we also noted (Tables S1-3).…”

Section: Discussionmentioning

confidence: 99%

HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

et al. 2022

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Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.

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Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Cited by 26 publications

References 49 publications

Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia

Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

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