Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells

Siriboonpiputtana, Teerapong; Zeisig, Bernd B.; Zarowiecki, Magdalena; Fung, Tsz Kan; Mallardo, Maria; Tsai, Chiou-Tsun; Lau, Priscilla Nga Ieng; Hoang, Quoc; Veiga, Pedro Mota; Barnes, Josephine; Lynn, Claire; Wilson, Amanda; Lenhard, Boris; So, Chi Wai Eric

doi:10.15252/embj.201797994

Cited by 23 publications

(18 citation statements)

References 65 publications

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“…In addition, HSC-derived AML showed higher frequency of LICs and lower responsiveness to chemotherapy treatment [48]. In agreement, Siriboonpiputtana et al [52] have demonstrated that self-renewal of LICs in HSC-derived AML is maintained through different molecular mechanisms compared to progenitor-derived AML, while phenotypically these two AMLs are indistinguishable. This suggests that genetically and phenotypically identical AMLs deriving from different cells of origin may react differently to the same treatment and emphasizes the importance of the "cellular context" for AML transformation.…”

Section: Cell Of Origin and "Cellular Context"mentioning

confidence: 60%

Acute Myeloid Leukemia: Aging and Epigenetics

Zjablovskaja

Florian

2019

Cancers

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Acute myeloid leukemia (AML) is an aggressive hematological disorder mainly affecting people of older age. AML initiation is primarily attributed to mutations in crucial cellular regulators such as epigenetic factors, transcription factors, and signaling genes. AML’s aggressiveness and responsiveness to treatment depends on the specific cell type where leukemia first arose. Aged hematopoietic cells are often genetically and/or epigenetically altered and, therefore, present with a completely different cellular context for AML development compared to young cells. In this review, we summarize key aspects of AML development, and we focus, in particular, on the contribution of cellular aging to leukemogenesis and on current treatment options for elderly AML patients. Hematological disorders and leukemia grow exponentially with age. So far, with conventional induction therapy, many elderly patients experience a very poor overall survival rate requiring substantial social and medical costs during the relatively few remaining months of life. The global population’s age is increasing rapidly without an acceptable equal growth in therapeutic management of AML in the elderly; this is in sharp contrast to the increase in successful therapies for leukemia in younger patients. Therefore, a focus on the understanding of the biology of aging in the hematopoietic system, the development of appropriate research models, and new therapeutic approaches are urged.

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Section: Cell Of Origin and "Cellular Context"mentioning

confidence: 60%

Acute Myeloid Leukemia: Aging and Epigenetics

Zjablovskaja

Florian

2019

Cancers

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“…Mutation of these residues to phenylalanine stabilizes the CDC73 interaction with β-catenin and enhances WNT signaling in gastric carcinoma cells [ 45 , 47 ]. A critical role for β-catenin in MLL rearranged leukemias prompted us to investigate this triple tyrosine to phenylalanine mutant, CDC73-Y290/293/315F (CDC73_3YF) (Figure 1A ) in MLL-AF9 transformed AML cells (Figure 1B ) [ 48 – 50 ]. As reported, CDC73_3YF displayed enhanced interaction with β-catenin compared to wild type CDC73 following transient transfection of HEK293T cells and immunoprecipitation (IP) of β-catenin ( Supplementary Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression ofHoxa9andMeis1in acute myeloid leukemia

et al. 2018

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The Polymerase Associated Factor 1 complex (PAF1c) is an epigenetic co-modifying complex that directly contacts RNA polymerase II (RNAPII) and several epigenetic regulating proteins. Mutations, overexpression and loss of expression of subunits of the PAF1c are observed in various forms of cancer suggesting proper regulation is needed for cellular development. However, the biochemical interactions with the PAF1c that allow dynamic gene regulation are unclear. We and others have shown that the PAF1c makes a direct interaction with MLL fusion proteins, which are potent oncogenic drivers of acute myeloid leukemia (AML). This interaction is critical for the maintenance of MLL translocation driven AML by targeting MLL fusion proteins to the target genes Meis1 and Hoxa9. Here, we use a proteomics approach to identify protein-protein interactions with the PAF1c subunit CDC73 that regulate the function of the PAF1c. We identified a novel interaction with a histone H3 lysine 9 (H3K9) methyltransferase protein, SETDB1. This interaction is stabilized with a mutant CDC73 that is incapable of supporting AML cell growth. Importantly, transcription of Meis1 and Hoxa9 is reduced and promoter H3K9 trimethylation (H3K9me3) increased by overexpression of SETDB1 or stabilization of the PAF1c-SETDB1 interaction in AML cells. These findings were corroborated in human AML patients where increased SETDB1 expression was associated with reduced HOXA9 and MEIS1. To our knowledge, this is the first proteomics approach to search for CDC73 protein-protein interactions in AML, and demonstrates that the PAF1c may play a role in H3K9me3-mediated transcriptional repression in AML.

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“…β-catenin has been demonstrated as a critical regulator of the self-renewal and therapeutic target for various cancer stem cells including leukemia-initiating cells (LICs) (12,13). Casein kinase 1α (CK1α), encoded by CSNK1A1, is a classical negative regulator for the Wnt/β-catenin signaling pathway (14).…”

Section: Introductionmentioning

confidence: 99%

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

Huang

Gan

et al. 2020

Oncol Rep

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Enhancement of autophagy serves as a promising therapeutic strategy for cancer, including acute myeloid leukemia (AML). Casein kinase 1α (CK1α), encoded by CSNK1A1, regulates Wnt/β-catenin, p53 and other key signaling pathways, and is critically involved in tumor progression. However, the relationship and mechanism of CK1α with autophagy in AML still remain unclear. In the present study, it was found that AML patients had higher expression of CSNK1A1 mRNA than healthy donors. Furthermore, we analyzed 163 cases of AML patients in the LAML database of TCGA and found that AML patients with high CSNK1A1 had shorter overall survival than those with low or medium CSNK1A1 expression. Furthermore, we demonstrated that CK1α was a negative regulator of autophagy and apoptosis. Pharmacologic inhibition of CK1α using D4476 or CK1α knockdown via lentivirus-mediated shRNA suppressed proliferation and the clone formation by enhancing autophagic flux and apoptosis in AML cell lines as well as in patient blast cells. Intriguingly, D4476-induced cell death was aggravated in combination with an autophagy inhibitor, Spautin-1, suggesting that autophagy may be a pro-survival signaling. CK1α interacted with murine double minute 2 (MDM2) and p53, and CK1α inhibitor D4476 significantly upregulated p53 and phosphorylated 5' AMP-activated protein kinase (AMPK), and substantially inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Our findings indicate that CK1α promotes AML by suppressing p53 downstream of MDM2-mediated autophagy and apoptosis, suggesting that targeting CK1α provides a therapeutic opportunity to treat AML.

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Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells

Cited by 23 publications

References 65 publications

Acute Myeloid Leukemia: Aging and Epigenetics

Acute Myeloid Leukemia: Aging and Epigenetics

PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression ofHoxa9andMeis1in acute myeloid leukemia

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

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