Research & Publications
Programmed cell death is crucial for the development of multiple cell lineages and organs, as well as the maintenance of normal tissue homeostasis. Whereas pathologic cellular survival is seen in cancer and autoimmune diseases, excessive cellular demise is found in diseases such as neurodegeneration and myocardial infarction. The goal of the laboratory is to rigorously define and elucidate the cellular signaling network that dictates life and death in appropriate cellular contexts. This knowledge is basic to developing selective therapeutics.
Extensive Research Description
A core focus of the laboratory is the expansive family of BCL-2 proteins. They comprise an intricate network of guardian and executioner proteins that govern the core pathway for programmed cell death in mammals. The role of the pro-apoptotic pore forming BCL-2 proteins in the development, maintenance and chemoresistance of malignancy is a fundamental molecular process studied by the laboratory
Of particular interest is a poorly understood family member called BOK, which is present in one of the 20 most frequently deleted genomic regions in all human cancers. Current evidence supports a role for BOK not only in the canonical apoptosis pathway, but in other cellular homeostasis pathways, such as the response to ER stress. How BCL-2 family members like BOK integrate these so-called "day-jobs" into their regulation of cell viability is of great interest. Using conditional mouse knockouts, biochemistry and genetic screening, we hope to unravel these complicated cellular signaling pathways. This knowledge will be important in devising therapeutic strategies to overcome blocks in apoptosis.
The immune system has an incredible capacity to selectively deliver cytotoxic strikes to defined targets. Understanding the determinants of both immune cell and cancer cell survival is important to optimize immunotherapy. Here we employ highly translational, synthetic engineering approaches to improve adoptive cellular therapy. Primary human T cells, Natural Killer (NK) cells and Tumor infiltrating lymphocytes (TILs) are reprogrammed using a multifactor mRNA approach developed by our collaborator, Sherman M. Weissman, Sterling Professor of Genetics. Our efforts are further strengthened by close collaborations with the Yale New Haven Hospital’s Advanced Cell Therapy core and several clinical oncologists.
Leukemia; Lymphoma; Stem Cells; Immunotherapy, Adoptive; Cell Death; Apoptosis; Genes, bcl-2; Mutant Chimeric Proteins; Endoplasmic Reticulum Stress; Cellular Reprogramming
- OAB-033: Pre-clinical models of genetically heterogeneous multiple myeloma reveal mechanisms of immune escape and predict clinical immunotherapy outcomesLarrayoz M, Garcia-Barchino M, Celay J, Etxebeste A, Jimenez M, Perez C, Ordoñez R, Cobaleda C, Chesi M, Bergsagel L, Rodríguez-Otero P, Takahashi S, Katz S, Walensky L, Ruppert S, Lasater E, Amann M, Lasarte J, Kurilovich A, Cerchietti L, Agirre X, San-Miguel J, Paiva B, Prosper F, Martinez-Climent J. OAB-033: Pre-clinical models of genetically heterogeneous multiple myeloma reveal mechanisms of immune escape and predict clinical immunotherapy outcomes Clinical Lymphoma Myeloma & Leukemia 2022, 22: s19-s20. DOI: 10.1016/s2152-2650(22)00306-8.
- Abstract 294: BCL-2 family compensation regulates T cell homeostasis and reveals a BIM:BCL-W axis in T-ALLLudwig L, Roach L, Katz S, Fisher J, Burns M, Schnorenberg M, Bao R, Zewde M, Nakamura Y, Gutierrez A, Walensky L, LaBelle J. Abstract 294: BCL-2 family compensation regulates T cell homeostasis and reveals a BIM:BCL-W axis in T-ALL Cancer Research 2018, 78: 294-294. DOI: 10.1158/1538-7445.am2018-294.
- Bok Promotes Erythropoiesis in a Mouse Model of Myelodysplastic SyndromeKang S, Perales O, Michuad M, Katz S. Bok Promotes Erythropoiesis in a Mouse Model of Myelodysplastic Syndrome Blood 2017, 130: 922-922. DOI: 10.1182/blood.v130.suppl_1.922.922.
- SOX11 Cooperates with CCND1 in Mantle Cell Lymphoma PathogenesisKuo P, Jiang Z, Perumal D, Leshchenko V, Lagana' A, Katz S, Walensky L, Shaknovich R, Ye B, Parekh S. SOX11 Cooperates with CCND1 in Mantle Cell Lymphoma Pathogenesis Blood 2015, 126: 1253-1253. DOI: 10.1182/blood.v126.23.1253.1253.
- Abstract 2367: Neural progenitor cells deficient in BAX and BAK manifest progressive hyperplasia and tumorigenesisKatz S, Fisher J, Bronson R, Ligon K, Walensky L. Abstract 2367: Neural progenitor cells deficient in BAX and BAK manifest progressive hyperplasia and tumorigenesis Cancer Research 2012, 72: 2367-2367. DOI: 10.1158/1538-7445.am2012-2367.
- Abstract 1775: Therapeutic reactivation of cell death in refractory hematologic cancers using a broad spectrum BIM BH3 death helixLaBelle J, Katz S, Bird G, Gavathiotis E, Stewart M, Fisher J, Godes M, Walensky L. Abstract 1775: Therapeutic reactivation of cell death in refractory hematologic cancers using a broad spectrum BIM BH3 death helix Cancer Research 2011, 71: 1775-1775. DOI: 10.1158/1538-7445.am2011-1775.
- A Stapled BIM BH3 Helix Restores Apoptosis In Bim-Null Mantle Cell LymphomaKatz S, Labelle J, Godes M, Fisher J, Bird G, Walensky L. A Stapled BIM BH3 Helix Restores Apoptosis In Bim-Null Mantle Cell Lymphoma Blood 2010, 116: 437-437. DOI: 10.1182/blood.v116.21.437.437.
- Structural Analysis of a BAX-BIM SAHB Complex Reveals a Novel BH3 Interaction Site on BAX for Therapeutic Activation of ApoptosisGavathiotis E, Suzuki M, Davis M, Pitter K, Bird G, Katz S, Tu H, Kim H, Cheng E, Tjandra N, Walensky L. Structural Analysis of a BAX-BIM SAHB Complex Reveals a Novel BH3 Interaction Site on BAX for Therapeutic Activation of Apoptosis Blood 2008, 112: 300-300. DOI: 10.1182/blood.v112.11.300.300.
- Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease.LaBelle J, Fisher J, Katz S, Bird G, Lawrence C, Silverstein A, Walensky L. Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease. Blood 2007, 110: 524-524. DOI: 10.1182/blood.v110.11.524.524.