title: Dissecting thein vivoleukemogenic potency of BCLxl.
abstract: Overexpression of anti-apoptotic members of the BCL2 family has been found in all types of cancer. A member of the family, BCLxl (B-cell lymphoma extra-large), is known to be associated with the progression of leukemogenesis. In the present study, we focused on understanding the domains of BCLxl responsible forin vivooncogenic potency. To this end, we utilized engineered BCLxl proteins with alternative transmembrane domains (TM) or chimeric BCLxl proteins containing domains from a less potent BCL2-like protein, BCLb. As expected, mice receiving MYC-only expressing bone marrow develop leukemia by 100 days, whereas co-expression of MYC with wild-type BCLxl led to aggressive myeloid leukemia with an average latency of ~25 days. Interestingly, mice injected with bone marrow co-expressing MYC and BCLxl targeted specifically to either mitochondria or ER also succumbed to leukemia with an average latency of ~25 days. Further, our study was extended to examine the role of the BH4 domain in driving potent leukemogenesis. Mice injected with bone marrow co-expressing MYC and BCLb succumb to leukemia in an average of ~55 days, but interestingly a BCLxl protein containing only the loop region of BCLb drove MYC-induced leukemogenesis with the same latency as wild-type BCLxl. These data suggest that the localization of exogenous BCLxl to either mitochondria or ER is not a steadfast dictator ofin vivooncogenic potency. Further, our findings suggest that the loop domain of BCLb and BCLxl is not responsible for dictating thein vivoleukemogeneic potency. This study provides further mechanistic details into the biochemical functions of BCLxl.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202.
authors.forename: Kumar
authors.initials: K
authors.lastname: Saurabh
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202 ; Department of Bioengineering, University of Louisville, Louisville, KY 40292.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Scherzer
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202.
authors.forename: Amy
authors.initials: A
authors.lastname: Song
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Yip
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202 ; Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202 ; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Chi
authors.initials: C
authors.lastname: Li
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202 ; Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202 ; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
keywords: BCL2L1; BCL2L10; BH4; MYC; apoptosis; leukemia