Interrogating cancer drivers: Mutant TP53 as a therapeutic target in hypodiploid B-cell acute lymphoblastic leukemia

25 Jan 2022
12:00 PM ET
Speaker:Ernesto Diaz-Flores, Ph.D.
Moderator:Jackie Oberst, Ph.D.

Jan

2022

12:00

Ernesto Diaz-Flores, Ph.D.Speaker

Jackie Oberst, Ph.D.Moderator

This webinar is brought to you by the Science/AAAS Custom Publishing Office.

In the last few years, interrogation of the role of altered genes in cancer has been greatly facilitated by the use of CRISPR/Cas. This gene-editing approach is a key research tool for modulating gene expression (knockout and knockin) efficiently and precisely. However, this approach can be limited depending on the cell type (hard-to-transduce, or primary cells). Such limitations are a challenging roadblock to advancing studies of a wide spectrum of malignant cells.

Patients with hypodiploid B-cell acute lymphoblastic leukemia (B-ALL) present with very poor prognosis (5-year event free survival <29%). These cells have been shown to exhibit mutations in p53 in >90% of cases (Diaz-Flores et al., Cancer Research, 2019). To better understand the mechanism of resistance that arises from p53 mutations, we wished to generate isogenic hypodiploid cell lines (including NALM-16) deficient in p53 and with knocking alleles of p53 wildtype or different mutant versions.

This seminar will cover the steps taken to go from 1%–2% lentiviral transduction efficiency to >95% in hard-to-transduce hypodiploid cell lines and primary cells. We will present how we were able to quickly and gently enrich transduced clones to allow such high transduction efficiency and the generation of knockouts for further studies.

During the webinar, the viewers will:

Discover the challenges and opportunities behind creating isogenic, hard-to-transduce hypodiploid cell lines and primary cells
Obtain insights into how different prepackaged CRISPR guide RNA lentiviruses require different measurable conditions for efficient transduction
Learn how early selection of purified viable cells can greatly enhance downstream applications, including the generation of patient-derived xenografts
Be able to ask questions during the live broadcast.

This webinar will last for approximately 60 minutes.

SPEAKER BIO

Ernesto Diaz-Flores, Ph.D.

University of California, San Francisco
San Francisco, CA

As a leukemia researcher, Dr. Flores’ ultimate goal is to find new cures for high-risk leukemia through an understanding of the mechanisms mediating leukemogenesis. During his time as assistant professor at the University of California, San Francisco, he has identified B-cell lymphoma 2 (BCL-2) as a promising therapeutic target and validated venetoclax as an effective drug against this leukemia. These studies contributed to the first clinical trial of venetoclax in pediatric acute lymphoblastic leukemia (ALL). In follow-up work, Dr. Flores provides evidence for a highly effective combinatorial therapy (Pariury et al., submitted) as well as biomarkers or response to inotuzumab immunotherapy (Benhert et al., submitted). His current work focuses on studying pharmacological and immunotherapeutic opportunities for targeting mutant p53 in the context of acute leukemia. This work represents a new paradigm in the field of p53 and hypodiploid leukemia and is expected to bring novel treatments to the clinic.

MODERATOR BIO

Jackie Oberst, Ph.D.

Science/AAAS
Washington, DC

Dr. Oberst did her undergraduate training at the University of Maryland, College Park, and her Ph.D. in Tumor Biology at Georgetown University, Washington D.C. She combined her interests in science and writing by pursuing an M.A. in Journalism from the Philip Merrill College of Journalism at the University of Maryland, College Park. Dr. Oberst joined Science/AAAS in 2016 as the Assistant Editor for Custom Publishing. Before then she worked at Nature magazine, the Howard Hughes Medical Institute, The Endocrine Society, and the National Institutes of Mental Health.

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