Teresa M. Palomero Vazquez, PhD
My research program focuses on the elucidation of the genetic and molecular bases of T-cell leukemia and lymphoma, with special interest in the development of targeted therapies for the treatment of these aggressive hematologic tumors.
During my early research career as a postdoctoral associate in the Dana Farber Cancer Institute under the supervision of Dr Thomas Look I participated in pioneer work in the development of the ChIP-on-chip technique in collaboration with Dr. Rick Young at the Broad Institute and applied this method to the characterization of the transcriptional regulatory networks downstream of the TAL1 oncogene in T-cell acute lymphoblastic leukemia (Palomero et al., Blood, 2006). After joining the faculty at Columbia University in 2005 I used gene expression profiling, ChIP-on-chip and ChIP-seq analysis for the identification of NOTCH1 direct target genes responsible for the transformation of T-cell progenitors (Palomero et al., PNAS 2006; Palomero et al., Nat Med 2007; Margolin et al., PNAS 2009; Real et al., Nat Med 2009) and identified mutations in PTEN as responsible for resistance to gamma secretase inhibitor therapy in T-ALL (Palomero et al., Nat Med 2007) and RUNX1 as a novel tumor suppressor in T-ALL (Della Gatta et al, 2012).
Over the last years I have leveraged the power of next generation sequencing approaches to identify novel oncogenes and tumor suppressors in T-ALL (van Vlierberghe and Palomero et al, 2009) and peripheral T-cell lymphomas (Palomero et al., Nat Genet 2014; da Silva Almeida et al., Nat Genet, 2015) and drivers of resistance to chemotherapy in relapsed leukemias (Tzoneva et al., Nat Med 2013; Oshima et al., PNAS 2016).
My current research focuses on the elucidation of the oncogenic mechanisms driven by these genetic alterations, the development of genetically manipulated mouse models of T-cell lymphoma and the therapeutic targeting of key oncogenic pathways responsible for T-cell transformation.
Peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis. We performed a systematic analysis of the genetic alterations responsible for PTCL transformation using a combination of whole exome sequencing of tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing of candidate genes. These analyses verified the presence of recurrent mutations in the TET2 tumor suppressor gene in PTCLs and identified recurrent mutations in the RHOA small GTPase gene including a highly prevalent RHOA G17V allele in this disease identified in 70% of angioimmunoblastic T-cell lymphomas (AITL) and almost 20% of not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, our results demonstrated that RHOA G17V inhibits RHOA signaling via a GEF-trap mechanism. Thus, RHOA G17V effectively binds to active GEFs but fails to load GTP and to interact with downstream effector factors, which results in impaired RHOA signaling.
Our central hypothesis is that the PTCL RHOA G17V mutation acts as negative regulators of RHOA signaling and contributes to T-cell transformation by disrupting key mechanisms that control cell signaling, proliferation, survival and migration. Moreover we postulate that RHOA G17V specifically cooperates with TET2 mutations in the pathogenesis of AITL. The focus of our research is (i) to identify signaling factors mediating the oncogenic activity of RHOA G17V in T-cells, (ii) to characterize the role and mechanisms of RHOA G17V in T-cell transformation and finally (iii) to analyze the oncogenic effects of RHOA G17V in the pathogenesis of AITL in vivo.
Oshima K, Khiabanian H, da Silva-Almeida AC, Tzoneva G, Abate F, Ambesi-Impiombato A, Sanchez-Martin M, Carpenter Z, Penson A, Perez-Garcia A, Eckert C, Nicolas C, Balbin M, Sulis ML, Kato M, Koh K, Paganin M, Basso G, Gastier-Foster JM, Devidas M, Loh ML, Kirschner-Schwabe R, Palomero T#, Rabadan R#, Ferrando AA# (2016) Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. Sep 21.
(# co-senior authors)
Cortés JR, Palomero T. The curious origins of angioimmunoblastic T-cell lymphoma (2016). Curr Opin Hematol. Jul;23(4):434-43.
da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, Vermeer MH, Rabadan R#, Ferrando A#, Palomero T#. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome (2015) Nat Genet. 47(12):1465-70. PMID: 26551667 (# co-senior authors)
Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navás D, Cordon-Cardo C, Clappier E, Soulier J, Ferrando AA.A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia (2014) Nat Med. 20(10):1130-7. PMID: 25194570
Palomero T*, Couronné L*, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, Carpenter Z, Abate F, Allegretta M, Haydu JE, Jiang X, Lossos IS, Nicolas C, Balbin M, Bastard C, Bhagat G, Piris MA, Campo E, Bernard OA, Rabadan R, Ferrando AA. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas (2014) Nat Genet. 46(2):166-70. PMID: 24413734
(*Palomero T and Couronné L contributed equally to this work)
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#, Rabadan R#, Ferrando A#. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL (2013) Nat Med. 19(3):368-71. PMID: 23377281
(# co-senior authors)
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, Ferrando AA. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL (2012) Nat Med. 18(3):436-40. PMID: 22366949
De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, 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 D, Cavé H, Dastugue N, Raimondi S, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation (2010) Nat Med. 16(11):1321-7. PMID: 20972433
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 PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A. PHF6 mutations in T-cell acute lymphoblastic leukemia (2010) Nat Genet. 42(4):338-42. PMID: 20228800
(*Van Vlierberghe P and Palomero T contributed equally to this work)
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker JC, Dominguez M, Ferrando AA. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia (2007) Nat Med. 13(10):1203-10. PMID: 17873882
Palomero T, Lim WK, Odom DT, 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 AA. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth (2006) Proc Natl Acad Sci U S A. 103(48):18261-6. PMID: 17114293
Palomero T, Odom DT, O'Neil J, Ferrando AA, Margolin A, Neuberg DS, Winter SS, Larson RS, Li W, Liu XS, Young RA, Look AT. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia (2006) Blood 108(3):986-92. PMID: 16621969