Adolfo Ferrando, Ph.D.
 E-Mail: af2196@columbia.edu Phone: 212-851-4611
Assistant Professor
 Location: ICRC 505A  

Ferrando Lab Research Summary

Our group seeks to understand the molecular mechanisms that promote and sustain the malignant proliferation and survival of leukemic cells.  We are engaged in a number of projects analyzing the functions of specific oncogenes and their role in the pathogenesis of childhood leukemia using a combination of genomic technologies, biochemical and genetic analysis. The lab’s research is focused on the cellular and molecular biology of T-cell lymphoblastic leukemia, an aggressive malignancy that results from the cancerous transformation of the progenitors that normally generate the cellular elements of the immune system. Our goal is to uncover the mechanisms that operate in leukemic cells to disrupt nor mal cell growth and survival, and to translate this understanding on to clinical use through the identification of therapeutic targets for the design of highly effective and less toxic, molecularly-tailored antileukemic drugs.

Role of transcription factor oncogenes in T-cell leukemia.

HOX11 and HOX11L2: oncogenic factors with relevant prognostic significance. Over the last years we have used DNA microarrays, a technology based on the information gained from the sequencing of the human genome, to study the role of T-cell leukemia oncogenes. In these microarray studies, the activity of thousands of genes is measured simultaneously, giving us a genome wide picture of the molecular pathways operating in the leukemic cells.  Using these genomic tools we have uncovered that human T-cell leukemia can result from the activation of four different oncogenic pathways, which are controlled by a limited number of T-cell oncogenes such as TAL1, HOX11 and HOX11L2. Importantly, we have demonstrated that patients whose leukemic cells harbor the HOX11 oncogene have a very favorable clinical prognosis when treated with chemotherapy, and can be safely spared the toxic effects associated with more intensive treatments such as bone marrow transplantation. Since HOX11 and HOX11L2 are regulators which contribute malignant transformation by binding to DNA and controlling expression of effector genes, we are using a novel genomic tool called ChIP on chip to spot the specific set of genes which they bind to through the genome. We predict that the identification of direct target genes downstream of HOX11 and HOX11L2 will uncover critical factors for the proliferation and survival of the leukemic cells, which can be exploited for the development of novel antileukemic drugs.

NOTCH1: oncogene and Achilles’ heel of the malignant clone. Based on our observation that T-cell leukemia oncogenes seem to operate by disrupting the mechanisms which control the development of normal progenitor cells in the immune system, we hypothesized that aberrant activation of NOTCH1, a critical gene required for the formation of the immune system, might play an important role in the pathogenesis of T-cell leukemia. This hypothesis was proven right when we sequenced the NOTCH1 gene and found that over 50% of human T-cell leukemias harbor mutations in NOTCH1, which result in oncogenic overactivation of this critical signaling molecule. Importantly, NOTCH1 had been extensively studied for years because of its important function in the development of the brain and the formation of the immune system. These basic research studies had shown that truncation of the NOTCH1 protein is required for its activation; and that inhibition of NOTCH1 signaling can be effectively achieved by blocking the gamma-secretase protein complex which catalyzes this cleavage. The induction of growth arrest and programmed cell death in leukemic cells treated in vitro with these NOTCH signaling inhibitors demonstrated the essential role of NOTCH1 signaling for the proliferation and survival of these malignant cells; and prompted the expeditious initiation of a clinical trial to test the efficacy of these NOTCH signaling inhibitors in the treatment of chemotherapy resistant T-cell leukemia.  These exciting results have opened many new questions: What are the molecular mechanisms that operate downstream of NOTCH activation? Are there alternative mechanisms of NOTCH activation other than NOTCH1 mutations operating in human T-cell leukemias? Will leukemic cells eventually become resistant to the treatment with currently available NOTCH1 inhibitors? Can we predict which leukemia patients can be effectively treated with drugs targeting the NOTCH signaling pathway? Are there additional drug targets in the NOTCH1 signaling pathway which can be exploited to develop novel antileukemic drugs?  Answering these questions is critical to understand the mechanisms of T-cell transformation and to optimize the therapeutic use of NOTCH signaling inhibitors in human T-cell leukemias and is the main focus of the research effort currently ongoing in our lab.

 

Selected Publications:

  1. 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
     

  2. Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, Lin S, Prochownik E, Trede NS, Zon LI, Look AT. Myc-induced T cell leukemia in transgenic zebrafish. Science, 2003, 299:887-90.
     

  3. Ferrando AA, Armstrong SA, Neuberg DS, Sallan SE, Silverman LB, Golub TR, Korsmeyer SJ, and Look AT.. Gene expression signatures in T lineage and B-precursor MLL-rearranged acute leukemias: Dominance of HOX dysregulation. Blood, 2003,102:262-268.
     

  4. Ferrando A. A., Herblot S., Palomero T, Hansen M, Hoang T. Fox E A, Look A. T. Biallelic transcriptional activation of oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Blood.  2004 ;103: 1909-11.
     

  5. Ferrando AA, Neuberg DS, Dodge RK, Paietta E, Larson RA, Wiernik PH, Rowe JM, Caligiuri MA, Bloomfield CD, and Look AT.  Prognostic Importance of HOX11 Oncogene Expression in Adults with T-Cell Acute Lymphoblastic Leukemia. The Lancet. 2004; 363: 535-6.
     

  6. 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.
     

  7. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando A, Downing JR, Jacks T, Horvitz HR and Golub TR. MicroRNA expression profiles classify human cancers Nature 2005, 435, 834-838
     

  8. Palomero T, Barnes KC, Real PJ, Glade Bender JL, Sulis ML, Murty VV, Colovai AI, Balbin M and Ferrando AA CUTLL1, A Novel Human T-Cell Lymphoma Cell Line With t(7;9) Rearrangement, Aberrant NOTCH1 Activation And High Sensitivity To g-Secretase Inhibitors. Leukemia. 2006 Jul;20(7):1279-87
     

  9. Palomero T, Odom DT, O’Neil J, Ferrando A, Margolin A, Neuberg AS, Winter S, Larson RS, Li W, Liu XS, Young RA and Look AT. Transcriptional Regulatory Networks Downstream of TAL1/SCL in T-cell Acute Lymphoblastic Leukemia. Blood 2006 Aug 1;108(3):986-92
     

  10. Palomero T, McKenna K,  O-Neil J, Galinsky I, Stone R, Suzukawa K, Stiakaki E, Kalmanti M, Fox EA, Caligiuri MA, Aster JC, Look AT and Ferrando A. Activating mutations in NOTCH1 in AML and lineage switch leukemias. Leukemia, 2006 ;20:1963-6
     

  11. 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. PNAS, 2006;103:18261-6.
     

  12. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, Kee BL, Ferrando A, Miele L, Aifantis I.  Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med. 2007;13:70-77.
     

  13. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, Ferrando A, Aifantis I. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med. 2007 in press
     

  14. 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 in press