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Hubo Li, Brenton G Mar, Huadi Zhang, Rishi V Puram, Francisca Vazquez, Barbara A Weir, William C Hahn, Benjamin Ebert, David Pellman
Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale shRNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein...
October 18, 2016: Blood
Qiang Liu, Longgui Chen, Jennifer M Atkinson, David F Claxton, Hong-Gang Wang
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation...
2016: Cell Death & Disease
Rebecca A Bilardi, Natasha S Anstee, Stefan P Glaser, Mikara Robati, Cassandra J Vandenberg, Suzanne Cory
Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model...
2016: Cell Death & Disease
Craig E Eckfeldt, Emily J Pomeroy, Robin D W Lee, Katherine S Hazen, Lindsey A Lee, Branden S Moriarity, David A Largaespada
Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect...
August 20, 2016: Oncotarget
Qiang Zhang, Lei Zeng, Chengcheng Zhao, Ying Ju, Tsuyoshi Konuma, Ming-Ming Zhou
Histone lysine acylations play an important role in the regulation of gene transcription in chromatin. Unlike histone acetyl-lysine, molecular recognition of a recently identified crotonyl-lysine mark is much less understood. Here, we report that the YEATS domain of AF9 preferentially binds crotonyl-lysine over acetyl-lysine in histone H3. Nuclear magnetic resonance structural analysis reveals that crotonyl-lysine of histone H3 lysine 18 is engulfed deep in an aromatic cage of the YEATS domain where the carbonyl oxygen of crotonyl-lysine forms a hydrogen bond with the backbone amide of protein residue Tyr78...
September 6, 2016: Structure
Jing Xu, Li Li, Jie Xiong, Aaron denDekker, Andrew Ye, Hacer Karatas, Liu Liu, He Wang, Zhaohui S Qin, Shaomeng Wang, Yali Dou
Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA-binding and cofactor interacting domains at the N terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program...
2016: Cell Discovery
Tatsuro Watanabe, Patricia Ernst
In this issue of Cancer Cell, Stavropoulou et al. report that expression of the MLL-AF9 fusion results in acute myelogenous leukemia (AML) with different behaviors depending on cell context, which leads them to identify a transcriptional signature surprisingly resembling that of the epithelial-to-mesenchymal (EMT) transition, correlating with aggressiveness of disease.
July 11, 2016: Cancer Cell
Jinxing Xia, Zheng Hu, Satoshi Yoshihara, Yuying Li, Chun-Hui Jin, Shulian Tan, Wei Li, Qingfeng Chen, Megan Sykes, Yong-Guang Yang
The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system...
August 2016: EBioMedicine
Margherita Ghisi, Lev Kats, Frederick Masson, Jason Li, Tobias Kratina, Eva Vidacs, Omer Gilan, Maria A Doyle, Andrea Newbold, Jessica E Bolden, Kirsten A Fairfax, Carolyn A de Graaf, Matthew Firth, Johannes Zuber, Ross A Dickins, Lynn M Corcoran, Mark A Dawson, Gabrielle T Belz, Ricky W Johnstone
E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells...
July 11, 2016: Cancer Cell
Vaia Stavropoulou, Susanne Kaspar, Laurent Brault, Mathijs A Sanders, Sabine Juge, Stefano Morettini, Alexandar Tzankov, Michelina Iacovino, I-Jun Lau, Thomas A Milne, Hélène Royo, Michael Kyba, Peter J M Valk, Antoine H F M Peters, Juerg Schwaller
To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers...
July 11, 2016: Cancer Cell
Yana Pikman, Alexandre Puissant, Gabriela Alexe, Andrew Furman, Liying M Chen, Stacey M Frumm, Linda Ross, Nina Fenouille, Christopher F Bassil, Caroline A Lewis, Azucena Ramos, Joshua Gould, Richard M Stone, Daniel J DeAngelo, Ilene Galinsky, Clary B Clish, Andrew L Kung, Michael T Hemann, Matthew G Vander Heiden, Versha Banerji, Kimberly Stegmaier
Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts...
June 27, 2016: Journal of Experimental Medicine
Quan Wang, Qing-Chuan Zheng, Hong-Xing Zhang
Histone acetylation is a very important regulatory mechanism in gene expression in the chromatin context. A new protein family-YEATS domains have been found as a novel histone acetylation reader, which could specific recognize the histone lysine acetylation. AF9 is an important one in the YEATS family. Focused on the AF9-H3K9ac (K9 acetylation) complex (ALY) (PDB code: 4TMP) and a serials of mutants, MUT (the acetyllsine of H3K9ac was mutated to lysine), F59A, G77A, and D103A, we applied molecular dynamics simulation and molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculations to examine the role of AF9 protein in recognition interaction...
November 2016: Biopolymers
Ayako Ui, Akira Yasui
Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia...
April 25, 2016: Nucleus
Abel Sánchez-Aguilera, Simón Méndez-Ferrer
We recently reported that estrogens regulate survival, proliferation, and self-renewal of hematopoietic stem cells and progenitors via estrogen receptor-α activation. Through its proapoptotic effect on malignant progenitors, tamoxifen treatment blocks the development of JAK2 (V617F) -induced myeloproliferative neoplasms in mice and sensitizes MLL-AF9-induced leukemias to chemotherapy, without detrimental effects on normal hematopoiesis.
January 2016: Molecular & Cellular Oncology
Joydeep Ghosh, Michihiro Kobayashi, Baskar Ramdas, Anindya Chatterjee, Peilin Ma, Raghuveer Singh Mali, Nadia Carlesso, Yan Liu, David R Plas, Rebecca J Chan, Reuben Kapur
Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9...
July 1, 2016: Journal of Clinical Investigation
Karl Agger, Satoru Miyagi, Marianne Terndrup Pedersen, Susanne M Kooistra, Jens Vilstrup Johansen, Kristian Helin
Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using Jmjd2a, Jmjd2b, and Jmjd2c conditional triple-knockout mice, we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene...
June 1, 2016: Genes & Development
Sang-Nee Tan, Sai-Peng Sim, Alan S B Khoo
BACKGROUND: Genetic aberrations have been identified in nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains elusive. There are increasing evidences that the apoptotic nuclease caspase-activated deoxyribonuclease (CAD) is one of the players leading to translocation in leukemia. Oxidative stress, which has been strongly implicated in carcinogenesis, is a potent apoptotic inducer. Most of the NPC etiological factors are known to induce oxidative stress. Although apoptosis is a cell death process, cells possess the potential to survive apoptosis upon DNA repair...
2016: Cell & Bioscience
Hongxiang Zeng, Hao Gu, Chiqi Chen, Minle Li, Fangzhen Xia, Li Xie, Xiaoye Liu, Feifei Zhang, Xuemei Tong, Jiangbo Wang, Zhuo Yu, Junke Zheng
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs...
May 20, 2016: Oncotarget
Christopher Y Park
No abstract text is available yet for this article.
May 12, 2016: Blood
Men Yee Chiew, Nem Yun Boo, Kenny Voon, Soon Keng Cheong, Pooi Pooi Leong
Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia (AML), affects mostly young children and has poor prognosis. The mechanisms of treatment failure of AML-M5 are still unclear. In this study, we generated iPSC from THP-1 cells from a patient with AML-M5, using retroviruses encoding the pluripotency-associated genes (OCT3/4, SOX2, KLF4 and c-MYC). These AML-M5-derived iPSC showed features similar with those of human embryonic stem cells in terms of the morphology, gene expression, protein/antigen expression and differentiation capability...
May 17, 2016: Leukemia & Lymphoma
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