scholarly journals Targeting leukemia stem cells with HDAC inhibitors and modulators of the DNA damage response

2014 ◽  
Vol 3 (S1) ◽  
pp. S14-S15 ◽  
Author(s):  
S Grant
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Hdac Inhibitors ◽  
Leukemia Stem Cells ◽  
Damage Response

Enhancers of Polycomb EPC1 and EPC2 Prevent Accumulation of MYC to Sustain the Oncogenic Potential of MLL Leukemia Stem Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 400-400
Author(s):  
Xu Huang ◽  
Tim Somervaille
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Progenitor Cells ◽  
Dna Damage Response ◽  
Leukemia Cells ◽  
Leukemia Stem Cells ◽  
Oncogenic Potential ◽  
Damage Response ◽  
Stem And Progenitor Cells ◽  
Complex Components

Abstract Abstract 400 Dysregulation of the structure and function of chromatin is common in myeloid malignancy. We used a lentiviral screening strategy to target for knockdown ∼270 genes coding for chromatin regulatory proteins in human THP-1 AML cells. THP-1 cells harbor a t(9;11) translocation which is the cytogenetic hallmark of MLL-AF9, found in ∼5% of patients with AML. The strategy identified the EP400 chromatin complex components EPC1 and EPC2 as critical oncogenic co-factors in MLL leukaemia. Knockdown of both EPC1 and EPC2 in human MLL-mutated cell lines and of Epc1 and Epc2 in experimentally initiated murine MLL-AF9 AML cells led to loss of AML cell clonogenic potential, due to induction of apoptosis. The phenotype was rescued by forced expression of human EPC1 or EPC2 in Epc knockdown cells. Epc1 and Epc2 knockdown MLL-AF9 AML cells failed to initiate AML upon syngeneic transplantation into secondary murine recipients, while control cells initiated short latency leukemia. Likewise, xenogeneic transplantation of EPC1 or EPC2 knockdown primary human MLL-AF9 AML failed to engraft recipients, while control cells which engrafted every recipient to variable extent. In complete contrast, knockdown of EPC1 or EPC2 did not adversely impact on either the in vitro clonogenic or in vivo repopulating potential of primary murine KIT+ or human CD34+ normal haematopoietic stem and progenitor cells. These data demonstrate a remarkable selective dependency of MLL-mutated leukemia stem cells, but not normal hematopoietic stem and progenitor cells, on Epc1 and Epc2. EPC1 and EPC2 are part of an EP400 centred complex with a role in the DNA damage response. The complex is also known to associate with MYC. Consistent with a role for EPC containing complexes in the DNA damage response, Epc1 and Epc2 KD in both normal and leukemic cells induced γH2A.X. However, only in leukemia cells was a transcriptional signature of MYC activation noted together with accumulation of MYC protein, prior to induction of Bim and subsequent apoptosis. This observation reveals a novel mechanism operational in leukaemia cells but not normal myeloid cells by which protein levels of the critical cellular oncogene MYC are limited by EPC/EP400. This counterintuitive observation refines the paradigm for MYC in transformed cells: when the function of EPC and its associated EP400 complex components is inhibited, thus impairing the DNA damage response, MYC accumulates and sensitises cells to apoptotic death. Thus EPC1 and EPC2 are components of a complex which serves to prevent MYC accumulation in myeloid leukemia cells and their sensitisation to apoptosis, thus sustaining oncogenic potential. Therapeutic targeting of this complex may facilitate restoration of the natural tumour suppressor mechanisms that prevent cellular transformation by MYC and enhance chemosensitivity of AML cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Characterizing the DNA damage response in putative stem cells of resected normal lung and matched NSCLC patient samples

2017 ◽  
Vol 28 ◽  
pp. ii4
Author(s):  
T.M. Marti ◽  
C.C. Tièche ◽  
R. Peng ◽  
S.R.R. Hall ◽  
L. Froment ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Nsclc Patient ◽  
Normal Lung ◽  
Damage Response

scholarly journals Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

2018 ◽  
Vol 24 (24) ◽  
pp. 6583-6593 ◽  
Author(s):  
Peter W. Nagle ◽  
Nynke A. Hosper ◽  
Lara Barazzuol ◽  
Anne L. Jellema ◽  
Mirjam Baanstra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Organ Dysfunction ◽  
Dna Damage Response ◽  
Adult Stem Cells ◽  
Radiation Doses ◽  
Damage Response ◽  
Low Radiation Doses

scholarly journals DNA Damage Response/Repair in Cancer Stem Cells — Potential vs. Controversies

10.5772/61355 ◽  
2015 ◽  
Author(s):  
Maria Louka ◽  
Effrossyni Boutou ◽  
Vasiliki Bakou ◽  
Vassiliki Pappa ◽  
Anastasios Georgoulis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

2016 ◽  
Vol 186 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Kalpana Mujoo ◽  
E. Brian Butler ◽  
Raj K. Pandita ◽  
Clayton R. Hunt ◽  
Tej K. Pandita
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pluripotent Stem Cells ◽  
Damage Response ◽  
Ionizing Radiations

Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells

2013 ◽  
Vol 6 (259) ◽  
pp. ra5-ra5 ◽  
Author(s):  
J. Carreras Puigvert ◽  
L. von Stechow ◽  
R. Siddappa ◽  
A. Pines ◽  
M. Bahjat ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Systems Biology ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Damage Response

scholarly journals Distinct Regulatory Mechanisms and Functions for p53-Activated and p53-Repressed DNA Damage Response Genes in Embryonic Stem Cells

2012 ◽  
Vol 46 (1) ◽  
pp. 30-42 ◽  
Author(s):  
Mangmang Li ◽  
Yunlong He ◽  
Wendy Dubois ◽  
Xiaolin Wu ◽  
Jianxin Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Regulatory Mechanisms ◽  
Damage Response
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