Dr. Adolfo Ferrando Research

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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.

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Role of transcription factor oncogenes in T-cell leukemia.

 Human T-cell lymphoblastic leukemias are highly aggressive tumors.  Over the last decade, our group has been studying the genetic programs and molecular alterations responsible for uncontrolled growth, proliferation and survival in human leukemia cells. Using a combination of genomic tools for mutation detection and analysis of gene expression we initially defined different molecular groups of T-cell leukemia defined by the activation of key oncogenic factors and characterized by a unique signature of gene expression and different prognosis (Ferrando, Cancer Cell 2002). Following on this work, we contributed to the identification of mutations resulting in the aberrant activation of the NOTCH1 gene in over 50% of patients with T-cell leukemia (Weng and Ferrando, Science 2004). The fundamental importance of this finding resides in our capacity to block the activity of NOTCH1 with drugs known as gamma-secretase inhibitors. Over the last years, our lab has analyzed the oncogenic function of NOTCH1 and the antileukemic properties of blocking NOTCH1 signaling.  These studies have uncovered the role of NOTCH1 as a master regulator of cell growth and metabolism upstream in leukemic cells and identified the interaction of NOTCH1 with major oncogenic factors such as MYC and the PI3K-AKT pathway (Palomero, PNAS 2006; Margolin, PNAS 2009; Palomero, Nat Med 2007; Herranz et al. 2014; Herranz et al. Nat Med 2015; Sanchez-Martin et al. PNAS 2017). In addition, we have demonstrated that inhibition of NOTCH1 signaling can effectively reverse resistance to glucocorticoid therapy in T-cell leukemias (Real, Nat Med 2009).

Moreover, we have systematically analyzed the role of the TLX1 oncogene in the pathogenesis of T-ALL using a combination of genomic studies and animal models (De Keersmaecker, Nat Med 2010; Della Gatta, Nat Med 2012). Over the years our group has identified new tumor suppressor genes including WT1 (Tosello, Blood 2009), PHF6 (Van Vlierberghe, Nat Genet 2010), BCL11B (De Keersmaecker Nat Med 2010), RUNX1 (Della Gatta Nat Med 2012), ETV6 (Van Vlierberghe, J Exp Med 2011), SUZ12 and EZH2(Ntziachristos, Nat Med 2012) mutated and deleted in T-ALL, as well as pathognomonic mutations in RHOA, TCR signaling factors and VAV1 in peripheral T cell lymphomas (Palomero et al. Nat Genet 2013; da Silva Almeida et al. Nat Genet 2015; Abate et al. PNAS 2015). Finally, we have extensively analyzed the role and mechanisms of clonal evolution and resistance driving mutations in leukemia development and extensively characterized the role of NT5C2 as a driver of therapy resistance and therapeutic target at relapse (Tzoneva et al. Nat Med 2013; Oshima et al., PNAS 2016; Tzoneva et al. Nature 2018; Dieck et al. Cancer Cell 2018).

Current areas of research in the lab include the analysis of oncogenic programs and mechanisms of therapy resistance in human leukemia.