T-cell lymphoma molecular genetics group
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.
Dr. Palomero is Associate Professor of Pathology and Cell Biology at Columbia University. Over the last years she has 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). Her 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.
For a complete list of publications, please visit PubMed
Our laboratory is on the 6th floor of the Irving Cancer Research Center building, located between 166th and 167th streets on Saint Nicholas Ave. just across the street from the NYP Adult Emergency main entrance. Subway lines 1 or A C to the 168th Street Station.