University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Ernesto Diaz-Flores, PhD

Ernesto Diaz-Flores, PhD

Assistant Professor, Pediatrics/Oncology, UCSF

Cancer Center Program Memberships

Pediatric Malignancies

Research Summary

As a leukemia researcher, my ultimate goal is to find new cures for high-risk leukemia through an understanding of mechanisms mediating leukemogenesis. Through my training and experience accumulated over the last two decades, I am poised to bring novel discoveries to advance the field of leukemia research.

My graduate studies in molecular biology provided me expertise on T cell leukemia signaling and helped me identify critical mediators of lymphoid activation. For my postdoctoral studies I focused my efforts on in vivo models of leukemia. During my first postdoc in Dr. Shannon's lab, I dissected signal transduction alterations resulting from expression of mutant KrasG12D. My studies informed several therapeutic candidates for cells harboring what is considered an undruggable target. For my second postdoc, I joined Dr. Loh’s laboratory, where I studied the biochemical mechanisms of childhood hypodiploid leukemia. During this period, I made the observation that p53 is deregulated in low hypodiploid (LH) patient samples, which lead to the discovery of mutations in TP53 in LH B-ALL (>90%) with 40% of those mutations being present in germline. These findings are now used in the clinic to screen for TP53 mutations and Li-Fraumeni syndrome in patients with hypodiploid ALL.

Since promoted to assistant professor, I identified BCL-2 as a promising therapeutic target and carried all the experiments to identify and validate ABT-199 (Venetoclax) as an effective drug against this leukemia. I recently published this work as first and corresponding author. These studies contributed to the first clinical trial of ABT-199 (Venetoclax) for pediatric ALL opening this year. In follow up work as senior author, I provide evidence for a highly effective combinatorial therapy (submitted to Blood). Most recently, I have been implementing bioinformatics and systems biology analyses to my research. Thus, my current work builds upon my prior knowledge and efforts with proven translational relevance, but it also represents a completely new are of research and a new paradigm to bring novel treatments to the clinic.

Education

Universidad Complutense de Madrid, BS, 01/1997, Biochemistry
Universidad Autonoma de Madrid, PhD cum laude, 01/2003, Molecular Biology
University of California, San Francisco, (UCSF), Postdoc, 06/2010, Oncology
University of California, San Francisco, (UCSF), Postdoc, 03/2014, Oncology

Honors & Awards

  • 2019
    Faculty Learning and Development Award, University of California, San Francisco
  • 2016
    American Cancer Society Individual Research Award, American Cancer Society
  • 2015
    American Cancer Society Individual Research Award, American Cancer Society
  • 2006
    Young Investigator Award, Children's Tumor Foundation
  • 2007
    ASH Travel Award, American Society of Hematology

Selected Publications

  1. Osman J, Lambert J, Temple M, Devaux F, Favre R, Flaujac C, Bridoux D, Marque-Juillet S, Bruneel F, Mignon F, Diaz-Flores E, Hentgen V, Greder-Belan A, Azarian R, Koukabi M, Rousselot P, Raggueneau V, Maneglier B. Rapid screening of COVID-19 patients using white blood cell scattergrams, a study on 381 patients. Br J Haematol. 2020 Sep;190(5):718-722.
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  2. Diaz-Flores E, Comeaux EQ, Kim KL, Melnik E, Beckman K, Davis KL, Wu K, Akutagawa J, Bridges O, Marino R, Wohlfeil M, Braun BS, Mullighan CG, Loh ML. Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia. Cancer Res. 2019 May 1;79(9):2339-2351.
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  3. Pomeroy EJ, Lee LA, Lee RDW, Schirm DK, Temiz NA, Ma J, Gruber TA, Diaz-Flores E, Moriarity BS, Downing JR, Shannon KM, Largaespada DA, Eckfeldt CE. Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia. Oncogene. 2017 Jun 8;36(23):3263-3273.
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  4. Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, Richter-Pechanska P, Marovca B, Pail O, Jenni S, Diaz-Flores E, Chang BH, Brown TJ, Collins RH, Uhrig S, Balasubramanian GP, Bandapalli OR, Higi S, Eugster S, Voegeli P, Delorenzi M, Cario G, Loh ML, Schrappe M, Stanulla M, Kulozik AE, Muckenthaler MU, Saha V, Irving JA, Meisel R, Radimerski T, Von Stackelberg A, Eckert C, Tyner JW, Horvath P, Bornhauser BC, Bourquin JP. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood. 2017 Mar 16;129(11):e26-e37.
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  5. Sachs Z, Been RA, DeCoursin KJ, Nguyen HT, Mohd Hassan NA, Noble-Orcutt KE, Eckfeldt CE, Pomeroy EJ, Diaz-Flores E, Geurts JL, Diers MD, Hasz DE, Morgan KJ, MacMillan ML, Shannon KM, Largaespada DA, Wiesner SM. Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency. Haematologica. 2016 Oct;101(10):1190-1199.
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  6. Zhao Z, Chen CC, Rillahan CD, Shen R, Kitzing T, McNerney ME, Diaz-Flores E, Zuber J, Shannon K, Le Beau MM, Spector MS, Kogan SC, Lowe SW. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet. 2015 May;47(5):539-43.
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  7. Sachs Z, LaRue RS, Nguyen HT, Sachs K, Noble KE, Mohd Hassan NA, Diaz-Flores E, Rathe SK, Sarver AL, Bendall SC, Ha NA, Diers MD, Nolan GP, Shannon KM, Largaespada DA. NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia. Blood. 2014 Nov 20;124(22):3274-83.
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  8. Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, Poire X, Koval G, Shannon K, Reddy PL, Joseph L, Atallah EL, Dy P, Thomas SP, Smith SE, Doyle LA, Stadler WM, Larson RA, Stock W, Odenike O. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014 Jan 15;20(2):490-8.
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  9. Diaz-Flores E, Goldschmidt H, Depeille P, Ng V, Akutagawa J, Krisman K, Crone M, Burgess MR, Williams O, Houseman B, Shokat K, Sampath D, Bollag G, Roose JP, Braun BS, Shannon K. PLC-γ and PI3K link cytokines to ERK activation in hematopoietic cells with normal and oncogenic Kras. Sci Signal. 2013 Dec 3;6(304):ra105.
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  10. Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, Payne-Turner D, Churchman M, Andersson A, Chen SC, McCastlain K, Becksfort J, Ma J, Wu G, Patel SN, Heatley SL, Phillips LA, Song G, Easton J, Parker M, Chen X, Rusch M, Boggs K, Vadodaria B, Hedlund E, Drenberg C, Baker S, Pei D, Cheng C, Huether R, Lu C, Fulton RS, Fulton LL, Tabib Y, Dooling DJ, Ochoa K, Minden M, Lewis ID, To LB, Marlton P, Roberts AW, Raca G, Stock W, Neale G, Drexler HG, Dickins RA, Ellison DW, Shurtleff SA, Pui CH, Ribeiro RC, Devidas M, Carroll AJ, Heerema NA, Wood B, Borowitz MJ, Gastier-Foster JM, Raimondi SC, Mardis ER, Wilson RK, Downing JR, Hunger SP, Loh ML, Mullighan CG. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013 Mar;45(3):242-52.
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  11. Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, Lowe SW. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 2010 Jul 1;24(13):1389-402.
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  12. Lauchle JO, Kim D, Le DT, Akagi K, Crone M, Krisman K, Warner K, Bonifas JM, Li Q, Coakley KM, Diaz-Flores E, Gorman M, Przybranowski S, Tran M, Kogan SC, Roose JP, Copeland NG, Jenkins NA, Parada L, Wolff L, Sebolt-Leopold J, Shannon K. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. 2009 Sep 17;461(7262):411-4.
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  13. Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML. Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell. 2008 Oct 7;14(4):335-43.
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  14. Diaz-Flores E, Shannon K. Targeting oncogenic Ras. Genes Dev. 2007 Aug 15;21(16):1989-92.
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  15. Zhang Y, Diaz-Flores E, Li G, Wang Z, Kang Z, Haviernikova E, Rowe S, Qu CK, Tse W, Shannon KM, Bunting KD. Abnormal hematopoiesis in Gab2 mutant mice. Blood. 2007 Jul 1;110(1):116-24.
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  16. Van Meter ME, Diaz-Flores E, Archard JA, Passegue E, Irish JM, Kotecha N, Nolan GP, Shannon K, Braun BS. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood. 2007 May 1;109(9):3945-52.
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  17. Siliceo M, Garcia-Bernal D, Carrasco S, Diaz-Flores E, Coluccio Leskow F, Teixido J, Kazanietz MG, Merida I. Beta2-chimaerin provides a diacylglycerol-dependent mechanism for regulation of adhesion and chemotaxis of T cells. J Cell Sci. 2006 Jan 1;119(Pt 1):141-52. doi: 10.1242/jcs.02722. Epub 2005 Dec 13.
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  18. Cipres A, Carrasco S, Merino E, Diaz E, Krishna UM, Falck JR, Martinez-A C, Merida I. Regulation of diacylglycerol kinase alpha by phosphoinositide 3-kinase lipid products. J Biol Chem. 2003 Sep 12;278(37):35629-35.
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  19. Diaz-Flores E, Siliceo M, Martinez-A C, Merida I. Membrane translocation of protein kinase Ctheta during T lymphocyte activation requires phospholipase C-gamma-generated diacylglycerol. J Biol Chem. 2003 Aug 1;278(31):29208-15.
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  20. Flores I, Jones DR, Cipres A, Diaz-Flores E, Sanjuan MA, Merida I. Diacylglycerol kinase inhibition prevents IL-2-induced G1 to S transition through a phosphatidylinositol-3 kinase-independent mechanism. J Immunol. 1999 Jul 15;163(2):708-14.
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