Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Booth, Christopher A.G.; Barkas, Nikolaos; Neo, Wen Hao; Boukarabila, Hanane; Soilleux, Elizabeth; Giotopoulos, George; Farnoud, Noushin; Giustacchini, Alice; Ashley, Neil; Carrelha, Joana; Jamieson, Lauren E.; Atkinson, Deborah; Bouriez-Jones, Tiphaine; Prinjha, Rab K.; Milne, Thomas A.; Teachey, David T.; Papaemmanuil, Elli; Huntly, Brian J. P.; Jacobsen, Sten Eirik W.; Mead, Adam J.

doi:10.1016/j.ccell.2018.01.006

Cited by 53 publications

(58 citation statements)

References 48 publications

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“…In addition, increased EZH2 expression is also associated with tumor progression and poor prognosis of glioma, wherein both genetic and pharmacological EZH2 inhibition eradicate self-renewal and tumorigenicity of GSCs 131 , 142 , 143 . Additionally, EZH2 loss in combination with JAK2 V617F, RUNX1, TET2, or NRas G12D mutations can initiate myeloid or lymphoid malignancies 144 - 148 . Both gain- and loss-of-function PRC2 mutations can be tumorigenic 149 , 150 , indicating that chromatin remodeling factors drive cancer initiation and progression in a context-dependent manner.…”

Section: Chromatin Remodeling In Cscsmentioning

confidence: 99%

Stem cell programs in cancer initiation, progression, and therapy resistance

et al. 2020

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Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.

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Section: Chromatin Remodeling In Cscsmentioning

confidence: 99%

Stem cell programs in cancer initiation, progression, and therapy resistance

et al. 2020

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“…Another study conducted by Booth et al focused on inactivation of EZH2 and RUNX1 in progenitor rather than stem cells and found that combined inactivation enhances proliferation of early thymic progenitors in mice. Additional RAS-signaling pathway activation in form of an internal tandem duplication of Fms Related Receptor Tyrosine Kinase 3 (FLT3-ITD), frequently detected in AML and associated with a worse prognosis, resulted in aggressive lympho-myeloid leukemia [62]. EZH2 mutations also frequently co-occur with TET2 mutations [47,48,60].…”

Section: Mutual Exclusion and Concomitance Of Ezh2 And Other Leukemiamentioning

confidence: 99%

EZH2 in Myeloid Malignancies

Rinke

Chase

Cross

et al. 2020

Cells

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Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.

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“…[21][22][23], suggesting that PRC2 regulates normal HSCs in a dose-dependent manner. Although studies have shown that Ezh2 loss in combination with other lesions such as Jak2 V617F , Runx1, or Tet2 mutations promote myeloid or lymphoid malignancies (24)(25)(26)(27)(28), it remains unclear how different PRC2 dosages contribute to the development of hematopoietic malignancies under physiologic conditions.…”

Section: Introductionmentioning

confidence: 99%

Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation

et al. 2019

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Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics infl uence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS G12D mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-defi cient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2defi cient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS G12D to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-defi cient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-defi cient leukemiainitiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.

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Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Cited by 53 publications

References 48 publications

Stem cell programs in cancer initiation, progression, and therapy resistance

Stem cell programs in cancer initiation, progression, and therapy resistance

EZH2 in Myeloid Malignancies

Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation

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