1. A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition
- Author
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Catriona Jamieson, Maurizio Pellecchia, Wenxue Ma, Lawrence S.B. Goldstein, Alice Y. Shih, Maryla Krajewska, Kelly A. Frazer, Janine M. Low-Marchelli, Anil Sadarangani, John C. Reed, Karen Messer, Ifat Geron, Minya Pu, Christian L. Barrett, Dayong Zhai, Sheldon R. Morris, Lei Bao, Daniel Goff, Hye Jung E. Chun, Jessica M. Rusert, Thomas J. Hudson, Angela Court Recart, Kim Hien T. Dao, Peggy Wentworth, Mark D. Minden, Ryan Chuang, Christina Jamieson, Jason Gotlib, Kristen M. Smith, Jun Wei, Kamran Shazand, Giovanni Martinelli, Heather Leu, Marco A. Marra, Larisa Balaian, Daniel J. Goff, Angela Court Recart, Anil Sadarangani, Hye-Jung Chun, Christian L. Barrett, Maryla Krajewska, Heather Leu, Janine Low-Marchelli, Wenxue Ma, Alice Y. Shih, Jun Wei, Dayong Zhai, Ifat Geron, Minya Pu, Lei Bao, Ryan Chuang, Larisa Balaian, Jason Gotlib, Mark Minden, Giovanni Martinelli, Jessica Rusert, Kim-Hien Dao, Kamran Shazand, Peggy Wentworth, Kristen M. Smith, Christina A.M. Jamieson, Sheldon R. Morri, Karen Messer, Lawrence S.B. Goldstein, Thomas J. Hudson, Marco Marra, Kelly A. Frazer, Maurizio Pellecchia, John C. Reed, and Catriona H.M. Jamieson
- Subjects
Stromal cell ,Myeloid ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Genetics ,Humans ,Progenitor cell ,Protein Kinase Inhibitors ,030304 developmental biology ,0303 health sciences ,Leukemia ,Leukemia stem cells (LSCs) ,Myeloid leukemia ,Cell Biology ,medicine.disease ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,sense organs ,Bone marrow ,Stem cell ,Tyrosine kinase - Abstract
SummaryLeukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance. Notably, sabutoclax, a pan-BCL2 inhibitor, renders marrow-niche-resident BC LSCs sensitive to TKIs at doses that spare normal progenitors. These findings underscore the importance of alternative BCL2 family splice-isoform expression in BC LSC maintenance and suggest that the combinatorial inhibition of prosurvival BCL2 family proteins and BCR-ABL may eliminate dormant LSCs and obviate resistance.
- Published
- 2013
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