Genetic Aspects of Mantle Cell Lymphoma


Fri, Dec 06, 2013 1:00 pmuntilFri, Dec 06, 2013 2:00 pm


Life Sciences Building Auditorium
145 Bevier Road


(848) 932-5638

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Pedro Blecua Carrillo de Albornoz, Ph.D.

Institute of Computational BioMedicine
Weill Cornell Medical College, New York, NY

Abstract: Mantle Cell Lymphoma (MCL) is a rare disease, representing 2-7% of all non-Hodgkin's lymphomas in the Western world. To date, it remains incurable despite initial response to therapy. A novel therapeutic treatment has been used by Weill Cornell clinicians and is used in an ongoing clinical trial (in this particular case, N=1). This approach entails dual targeting of the cell cycle and the BCR pathway. For the former, a combination of the CDK4 inhibitor PD033291 and the Bortezomib drug is used. For the latter the drug of choice is Ibrutinib, which targets the Bruton's Tyrosine Kinase (BTK) and has been recently proven to work well in refractory MCL patients. After relapse from the initial PD/Bortezomib treatment, the single patient in the trial similarly relapsed after therapy with Ibrutinib. I extensively and rigorously analyzed whole exome and whole transcriptome sequencing data of tissues sampled at different stages of the combined treatment. With this data, for the first time in an MCL patient treated with Ibrutinib, I was able to show that there is a relapse specific missense C481S mutation in the binding pocket of Ibrutinib to BTK, in bone marrow and spleen tumors. Additionally, analysis of the copy number variations from the DNA tumor samples revealed an equally relapse specific hemizygous deletion on chr13q, containing the tumor suppressor RB1 - a key player in the cell cycle progression. Despite the loss of one copy, the transcription levels of RB1 remain unaltered, an effect attributable to 'dosage compensation'. Both the C481S mutation and the chr13q hemizyous deletion have been further supported by experimental findings from my collaborators.