Cell cycle checkpoints are implemented to safeguard our genome and the deregulation of which contributes to the pathogenesis of human cancers. Hence, it is of paramount importance to discover and interrogate novel key constituents of the mammalian DNA damage response network. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the essence of an intact S-phase checkpoint in maintaining genome integrity. Although basic framework of the S-phase checkpoint in multi-cellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome band 11q23 translocation disrupting the MLL gene results in poor prognostic leukemias that carry pathognomonic MLL fusions. MLL is a transcription co-activator that is best known to maintain HOX gene expression. The importance of HOXA gene deregulation in MLL leukemogenesis has been intensively investigated. However, physiological murine MLL leukemia knockin models indicated that MLL fusion-induced HOXA gene aberration alone is insufficient to initiate MLL leukemia. Therefore, further dysregulation must exit and contribute to the ultimate leukemia phenotype. Our recent studies demonstrated a close relationship between MLL and the regulation of mammalian cell cycle. MLL not only assists in the G1/S and G2/M phase transition during a normal cell division cycle but also executes the S-phase checkpoint upon DNA damage. We found that (1) MLL functions as a key effector of ATR-mediated S-phase checkpoint response, (2) activated ATR phosphorylates and thus stabilizes MLL, (3) upon checkpoint activation MLL accumulates at the late replication origin, methylates histone H3K4, and thus delays DNA replication, (4) MLL deficient cells exhibit defects in the S-phase checkpoint response, and (5) MLL fusions work as dominant negative mutants that compromise the integrity of S-phase checkpoint. Here we will determine the mechanisms by which MLL executes the S phase checkpoint response and examine whether and to what extent an S-phase checkpoint dysfunction contributes to MLL leukemogenesis. Our proposal connects MLL/MLL fusions to the S-phase checkpoint response network, which not only provides novel insights into the mammalian cell cycle checkpoint control but also shed light on the pathogenesis of poor prognostic human leukemias.
issue that directly impacts millions of lives and costs billions of dollars in the United States each year. Through a better understanding of the molecular pathogenesis of cancer, targeted therapeutics may be developed and eventually benefit advanced- stage cancer patients (1-2). Mixed lineage leukemia, resulted from chromosome translocation of the MLL gene, portends poor prognosis (3-6). Consequently, novel treatment strategies for this dreadful illness are urgently needed. My laboratory over the years has helped elucidate novel regulations and functions of the MLL protein (7-14). Cell cycle checkpoints safeguard our genome and compromised checkpoints contribute to the evolution of human cancer (15-18). Hence, we are particularly excited about our recent studies that link MLL to the DNA damage response network (14). Based on these findings, we propose to further investigate how MLL regulates the S-phase checkpoint and determine whether checkpoint dysfunction contributes to the MLL leukemogenesis. Data obtained from this current grant expect to provide novel insights concerning the mammalian DNA damage response network and shed light on the molecular pathogenesis of MLL leukemias.
|Hsieh, James J; Chen, David; Wang, Patricia I et al. (2017) Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma. Eur Urol 71:405-414|
|Hsieh, James J; Manley, Brandon J; Khan, Nabeela et al. (2017) Overcome tumor heterogeneity-imposed therapeutic barriers through convergent genomic biomarker discovery: A braided cancer river model of kidney cancer. Semin Cell Dev Biol 64:98-106|
|Becerra, Maria F; Reznik, Ed; Redzematovic, Almedina et al. (2017) Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma. Eur Urol Focus :|
|Nargund, Amrita M; Pham, Can G; Dong, Yiyu et al. (2017) The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma. Cell Rep 18:2893-2906|
|Dong, Yiyu; Manley, Brandon J; Becerra, Maria F et al. (2016) Tumor Xenografts of Human Clear Cell Renal Cell Carcinoma But Not Corresponding Cell Lines Recapitulate Clinical Response to Sunitinib: Feasibility of Using Biopsy Samples. Eur Urol Focus :|
|Voss, Martin H; Hsieh, James J (2016) Therapeutic Guide for mTOuRing through the Braided Kidney Cancer Genomic River. Clin Cancer Res 22:2320-2|
|Xu, Haiming; Valerio, Daria G; Eisold, Meghan E et al. (2016) NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis. Cancer Cell 30:863-878|
|Hakimi, A Ari; Reznik, Ed; Lee, Chung-Han et al. (2016) An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. Cancer Cell 29:104-116|
|Xu, Jianing; Pham, Can G; Albanese, Steven K et al. (2016) Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. J Clin Invest 126:3526-40|
|Takeda, Shugaku; Sasagawa, Satoru; Oyama, Toshinao et al. (2015) Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription. J Clin Invest 125:1203-14|
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