H. Phillip KOEFFLER

Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore
Distinguished Visiting Professor, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
Senior Consultant, Department of Haematology-Oncology, National University Hospital
Professor of Medicine, Cedars-Sinai Medical Center/UCLA

mdchpk[at]nus.edu.sg

The major focus of Prof Koeffler’s lab is identifying key DNA abnormalities in cancers and translating these findings into novel classifications and diagnoses. In addition, his team has begun looking for new therapeutic approaches based on the DNA changes that occur in these tumours. They have learned that not only do tumours have common unifying DNA changes, each have unique DNA changes. Therefore successful therapy will require the ability to survey rapidly the entire genome for alterations so that they can tailor therapy.

Research

We study the cellular and molecular biology of cancer – from genes to humans. Our basic research begins with whole exon deep sequencing of selected cancer subtypes. In particular, we are focused on samples from patients that have a recurrence of the cancer or the cancer is resistant to standard therapies. This affords the opportunity to identify genes associated with cancer progression. After identifying mutant genes, we study the functional consequences of these mutations by standard molecular and cellular biology techniques such as over-expression and silencing of the genes, and looking at the biological consequences both in vitro, as well as, in vivo in murine model systems. Where appropriate, we make germline alterations in mice to recapitulate the disease. We study the importance of these altered genes in human cancers, taking advantage of large collection of human tumor samples. Using these collections, we analyze for aberrant gene expression both at the RNA and protein levels (quantitive RT-PCR, Western blot, and immunohistochemistry including the use of large tissue arrays). The major cancers that we explore include: nasopharyngeal, lung, breast, and pancreatic cancers, glioblastoma multimultiforme (brain tumor), various sarcomas and hematopoietic malignancies.

Lab Members

Selected Publications

1. Lin D, Xu L, Ding L, Sharma A, Liu LZ, Yang H, Tan P, Vadgama J, Karlan B, Lester J Urban N, Schummer M, Doan N, Said JW, Sun H, Walsh M, Thomas CJ, Patel P, Yin D, Chan D, Koeffler HP. Genomic and functional characterizations of phosphodiesterase 4D in human cancers. PNAS. Mar 27 2013. [Epub ahead of print].

2. Lin D, Yin T, Koren-Michowitz M, Ding L, Gueller S, Gery S, Tabayashi T, Bergholz U, Kazi JU, Ronnstrand L, Stocking C, Koeffler HP. Adaptor protein LNK binds to and inhibits normal and leukemic FLT3. Blood, Oct18; 120(16): 3310-7, 2012. PMID 22942183.

3. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo a, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi t, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature, Sep11;478(7367):64-9, 2011.

4. Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park E, Kim YM, Hofmann WK, Herzong S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, Muschen M. BCL6 enables Ph+ acute lymphoblastic leukemia cells to survive BCR-ABL1 kinase inhibition. Nature 473(7347):384-8, 2011. PMID 21593872

5. Sherborne AL, Hosking FJ, Prasad RB, Kumar R, Koehler R, Vijayakrishnan J, Papaemmanuil E, Bartram CR, Stanulla M, Schrappe M, Gast A, Dobbins SE, Ma Y, Sheridan E, Taylor M, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Moorman AV, Harrison CJ, Tomlinson IP, Richards S, Zimmermann M, Szalai C, Semsei AF, Erdelyi DJ, Krajinovic M, Sinnett D, Healy J, Neira AG, Kawamata N, Ogawa S, Koeffler HP, Hemminki K, Greaves M, Houlston RS. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet. 2010, 42(6):492-4.

7. Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Stocking C, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Millr C, Harbott J, Ludwig W, Stanulla M, Schrappe M, Bartram C, Koeffler HP. Cloning of genes involved in chromosomal translocations by high resolution single nucleotide polymprphism genomic microarray. PNAS. 105(33):11921-6, 2008.

8. Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol. Cell. 22(3):375-82, 2006.

9. Chumakov AM, Grillier I, Chumakova E, Chih D, Slater J and Koeffler HP. Cloning of the Novel Human Myeloid-Cell-Specific C/EBP?- Transcription Factor.  Mol. Cell. Biol., 17(3) 1375-1386,1997.

10. Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ. Rearrangement of the p53 gene in human osteogenic sarcoma. PNAS, 84:7716-7719, 1987.