Research Faculty

Address
1130 St. Nicholas Avenue
Irving Cancer Research Center 402A
New York, NY 10032

Phone: 212-851-4611
Fax: 212-851-5256

af2196@columbia.edu
Education and Training
M.D. 1994, University of Oviedo, Asturias, Spain
Ph.D. 1999, University of Oviedo, Asturias, Spain
Postdoctoral research, 1999-2004, Dana-Farber Cancer Institute, Boston.

Affiliations
Herbert Irving Center
Institute for Cancer Genetics
Integrated Program


Collaborations
Dr. Andrea Califano, Columbia University
Dr. Raul Rabadan, Columbia University
Dr. Riccardo-Dalla Favera, Columbia University
Dr. Iannis Aifantis, New York University Medical Center
Dr. Ross Levine MSKCC
Dr. Carlos Cordon-Cardo, Mount Sinai School of Medicine
Dr. Ralph De Bernardinis, UTSW
Dr. Joan Guitar, Northeastern University
Dr. Ulrich Steidl, Albert Einstein College of Medicine
Dr. Elisabeth Paietta, Albert Einstein College of Medicine

Intl Collaborations
Dr. Elias Campo, Hospital Clinic in Barcelona, Spain
Dr. Miguel Angel Piris, Valdecilla Hospital, Santander Spain
Dr. Jules Meijerink Erasmus Medical Center in Rotterdam
Dr. Giuseppe Basso, University of Padua
Dr. Olivier Bernard, Institut Gustave Roussy, Villeuif, France
Training Activities
Cancer Biology
Immunology
Adolfo A. Ferrando, M.D., Ph.D.
Associate Professor of Pathology and Pediatrics
Leader Lymphoid Malignancies and Development Program, Herbert Irving Comprehensive Cancer Center
Associate Director for Research Pediatric Oncology Division
Research Summary

Oncogenic signaling pathways in T-cell transformation and chemotherapy resistance

T cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic tumor characterized by malignant transformation of immature T-cell progenitors. Despite the introduction of highly intensified chemotherapy protocols today 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease. Our research program combines genomic and systems biology approaches, biochemical analyses and experimental therapeutics to tackle this fundamental problem. What are the central oncogenic drivers of T-cell transformation in T-ALL? What are their downstream effector pathways and how do can target them for the development of new therapies? What are the mechanisms responsible for disease progression, relapse and chemotherapy resistance?

Constitutive activation of NOTCH signaling as result of activating mutations in the NOTCH1 gene is hallmark of T-ALL and offers a unique therapeutic opportunity as inhibitors of the -secretase complex, an aspartyl protease strictly required for NOTCH signaling, can effectively block oncogenic NOTCH1 activation. To elucidate specific genes and pathways controlled by oncogenic NOTCH in T-ALL we are deciphering the structure of the transcriptional network activated by NOTCH1 combining global gene expression profiling and ChIP-seq analysis, metabolomic profiling and animal models of NOTCH1 induced leukemia. These studies have already identified the MYC oncogene and the PI3K pathway as major effectors of NOTCH1 in T-ALL, identified mutational loss of PTEN as a key mediator of resistance to anti NOTCH1 therapies and highlighted a critical therapeutic interaction between NOTCH1 inhibitors and glucocorticoids. Moreover, and following on our identification of PTEN loss as a major mechanism of resistance to anti NOTCH1 therapies in T-ALL we have are using Pten conditional knockout mice to dissect the transcriptional, signaling and metabolic drivers of resistance to anti NOTCH1 therapies. These studies show a central role of cell metabolism in NOTCH1 induced transformation; highlight an oncogenic metabolic switch mechanism as a central mediator of resistance to anti NOTCH1 therapies in T-ALL and have identified new drugs and drug combinations specifically targeting these resistance mechanisms.

Glucocorticoids play a fundamental role in the treatment of ALL and primary glucocorticoid resistance is strongly associated with poor prognosis. An emerging hypothesis is that oncogenic transcriptional networks and signaling pathways can significantly modulate the therapeutic effect of glucocorticoids in human ALL. Based on these premises we have used a Systems Biology approach based on the reverse engineering of signaling circuits to identify molecular targets for the reversal of glucocorticoid resistance in T-ALL. This analysis identifies the AKT1 kinase gene as a critical mediator of resistance to glucocorticoids via direct phosphorylation and inactivation of the glucocorticoid receptor protein (NR3C1). The relevance of these results is highlighted by the capacity of MK2206, an AKT inhibitor in clinical trials for the treatment of cancer, to reverse glucocorticoid resistance in primary T-ALL samples in vitro and in vivo.

Finally, we are using whole exome sequencing and copy number analysis to address the role of Darwinian selection and clonal evolution as drivers of relapse and chemotherapy resistance. These studies demonstrate that most relapsed clones are related to but distinct from the dominant leukemia population at diagnosis and point to a critical role for selection of genetic alterations driving chemotherapy resistance in disease progression and relapse. Among these, mutations activating the NT5C2 nucleotidase, drive resistance to 6-mercaptopurine in 20% of relapsed T-ALLs, particularly in cases with early relapse and progression under therapy. Following on these results we are analyzing and modeling the process of selection, clonal evolution and resistance to therapy at relapse using ultradeep sequencing analyses of diagnostic, remission and relapsed leukemias; conditional and inducible knock-in mouse models of NT5C2 mutations; random mutagenesis and directed molecular evolution and in vivo shRNA screens to ask: what is the clonal architecture of primary and relapsed leukemias?; is clonal heterogeneity a driver of relapse?; how do relapse specific mutations relate to drug resistance in ALL?; and how does dose intensity, compliance and therapy complexity influence the process of clonal selection and therapy resistance?

Our research program brings together conceptual innovation, state of the art technologies, and Systems Biology approaches and addresses the most fundamental questions in T-ALL. The results of these experiments will ultimately bridge the knowledge gap on the basic mechanisms driving leukemia transformation, disease recurrence and therapy resistance and will be instrumental for the rational design of the next generation of targeted and personalized therapies in T-ALL.


Selected Publications

1. Palomero T, Couronné L, Khiabanian H, Kim M, Ambesi-Impiombato A, Perez-Garcia A, Carpenter Z, Abate F, Allegretta M, Haydu JE, Jiang X, Lossos IS, Nicolas, Balbin, Bastard, Bhagat, Piris MA, Campo E, Bernard O, Raul Rabadan R and Ferrando AA Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas Nat Genet in press

2. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, Perez-Garcia A, Rigo I, Castillo M, Indraccolo S, Paietta E, Racevskis J, Rowe JM, Tallman MS, Basso G, Meijerink JP, Cordon-Cardo C, Califano A and Ferrando AA Direct reversal of glucocorticoid resistance by AKT inhibition in T-ALL. Cancer Cell in press

3. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, Rigo I, LeDuc CA, Kelly K, Jalas C, Paietta E, Racevskis J, Rowe JM, Tallman MS, Paganin M, Basso G, Tong W, Chung WK and Ferrando AA. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 2013;122:2425-2432.

4. Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, Hadler M, Paietta E, Tallman MS, Rowe JM, Forne C, Rue M, and Ferrando AA Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia Blood 2013;122:74-82

5. Tzoneva G, Perez Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, Paietta E, Racevskis J, Rowe JM, Tallman MS, Paganin M, Basso G, Hof J, Kirschner-Schwabe R, Palomero T, Raul Rabadan R and Ferrando A Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL Nat Med 2013; 19:368-71

6. Haydu JE, De Keersmaecker K, Duff MK, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Ferrando A An activating intragenic deletion in NOTCH1 in human T-ALL Blood 2012; 119:5211-4.

7. Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW, De Keersmaecker K, Sole X, Xu L, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Meijerink JP, Califano A and Ferrando AA Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Medicine 2012; 18:436-40.

8. Ntziachristos, P, Tsirigos* A, Van Vlierberghe P., Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, Asp P, Hadler M, Rigo I, De Keersmaecker K, Patel J, Huynh T, Utro F, Poglio S, Samon JB, Paietta E, Racevskis J, Rowe JM, Rabadan R, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A*, Aifantis I* Genetic inactivation of the Polycomb complex PRC2 in T cell acute lymphoblastic leukemia Nat Medicine 2012; 18:298-303.

*Co-senior authorship

9. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M, Tosello V, Della Gatta G, Paietta E, Racevskis J, Luger SM, Rowe JM, Rue M and Ferrando AA ETV6 mutations in early immature human T-cell leukemias. J Exp Med 2011; 208:2571-9.

10. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, Nicolas C, Payer AR, Fernandez HF, Tallman MS, Paietta E, Melnick A, Vandenberghe P, Speleman F, Aifantis I, Cools J, Levine R, Ferrando A. PHF6 mutations in adult acute myeloid leukemia. Leukemia 2011; 25:130-4.

11. Keersmaecker K, Real P, Della Gatta G, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan P, Kelliher M, Kee B, Pandolfi PP, Kappes D, Gounari F, Petrie H, van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran E, Cavé H, Dastugue N, Raimondi S, Meijerink J, Cordon-Cardo C, Califano A, Ferrando AA The TLX1 oncogene drives aneuploidy in T-cell transformation Nat Med. 2010; 16:1321-7.

12. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik P, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando AA PHF6 mutations in T-cell acute lymphoblastic leukemia Nat Genet. 2010;42:338-42

13. Tosello V, Mansour MR, Barnes K, Paganin M, Sulis ML, Jenkinson S, Allen CG, Gale RE, Linch DC, Palomero T, Real P, Murty V, Yao X, Richards SM, Goldstone A, Rowe J, Basso G, Wiernik PH, Paietta E, Pieters R, Horstmann M, Meijerink JP, Ferrando A. WT1 mutations in T-ALL. Blood. 2009; 114:1038-1045

14. Real P, Tosello V, Palomero T, Castillo M, Hernando E, Stanchina E, Sulis ML, Barnes K, Sawai K, Homminga I, Meijerink J, Aifantis I, Basso G, Cordon-Cardo C, Ai W and Ferrando A. Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL. Nat Med 2009; 15:50-8.
15. Margolin A, Palomero T, Sumazin P, Califano A*, Ferrando A*, Stolovitzky G*. ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes. Proc Natl Acad Sci U S A. 2009; 106:244-9.

*Co-senior authorship

16. Sulis ML, Williams O, Palomero T, Tosello V, Pallikuppam S, Real PJ, Barnes K , Zuurbier L, Meijerink J and Ferrando A NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL Blood 2008;112:733-40.

17. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Mishra A, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker JC, Dominguez M and Ferrando A. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia Nat Med 2007;13:1203-10.

18. Palomero T, Lim WK, Odom D, Sulis ML, Real PJ, Margolin A, Barnes KC, O’Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando A. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A. 2006;103:18261-6.

19. Weng AP*, Ferrando AA *, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT and Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004 306(5694):269-71.
*Weng AP and Ferrando AA contributed equally to this work.

20. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT. Gene Expression Signatures Define Novel Oncogenic Pathways in T-Cell Acute Lymphoblastic Leukemia. Cancer Cell, 2002; 1:75-87


Current Projects

Role and mechanisms of oncogenic PI3K signaling in human leukemia
Identification and functional characterization of novel oncogenes and tumor suppressors in T-cell leukemias and lymphomas
Mechanisms of resistance in relapsed lymphoblastic leukemias

Honors and Awards

2000 Special Doctorate Award University of Oviedo

2007 Plenary Session Presentation at the American Society of Hematology 49th Meeting and Exposition, Atlanta, Georgia

2011 Outstanding Pilot Studies Award, Irving Institute for Clinical and Translational Research of Columbia University in the City of New York

2011 Harold & Golden Lamport Award for Excellence in Clinical Research - Columbia University in the City of New York

Committees , Council, and Professional Society Memberships

American Society of Hematology Membership

ECOG Laboratory Committee Membership
American Association for Cancer Research Membership

American Society for Clinical Investigation Membership
Basic Mechanisms of Cancer Therapeutics NIH Study Section Permanent Member

Leukemia and Lymphoma Society Translational Research Program Review Panel

Damon Runyon Foundation Fellowship Review Panel

Member of the editorial board of Leukemia, Section Editor

Member of the editorial board of Blood Cancer Journal, Deputy Editor

Member editorial board of Blood

Keywords

T-ALL, NOTCH1, PTEN, leukemia drug resistance, PHF6, ETV6, NT5C2


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