title: A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition.
abstract: Leukemia 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.
authors: Stem Cell Program, Department of Medicine, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors: Daniel J
authors: DJ
authors: Goff
authors: Angela
authors: A
authors: Court Recart
authors: Anil
authors: A
authors: Sadarangani
authors: Hye-Jung
authors: HJ
authors: Chun
authors: Christian L
authors: CL
authors: Barrett
authors: Maryla
authors: M
authors: Krajewska
authors: Heather
authors: H
authors: Leu
authors: Janine
authors: J
authors: Low-Marchelli
authors: Wenxue
authors: W
authors: Ma
authors: Alice Y
authors: AY
authors: Shih
authors: Jun
authors: J
authors: Wei
authors: Dayong
authors: D
authors: Zhai
authors: Ifat
authors: I
authors: Geron
authors: Minya
authors: M
authors: Pu
authors: Lei
authors: L
authors: Bao
authors: Ryan
authors: R
authors: Chuang
authors: Larisa
authors: L
authors: Balaian
authors: Jason
authors: J
authors: Gotlib
authors: Mark
authors: M
authors: Minden
authors: Giovanni
authors: G
authors: Martinelli
authors: Jessica
authors: J
authors: Rusert
authors: Kim-Hien
authors: KH
authors: Dao
authors: Kamran
authors: K
authors: Shazand
authors: Peggy
authors: P
authors: Wentworth
authors: Kristen M
authors: KM
authors: Smith
authors: Christina A M
authors: CA
authors: Jamieson
authors: Sheldon R
authors: SR
authors: Morris
authors: Karen
authors: K
authors: Messer
authors: Lawrence S B
authors: LS
authors: Goldstein
authors: Thomas J
authors: TJ
authors: Hudson
authors: Marco
authors: M
authors: Marra
authors: Kelly A
authors: KA
authors: Frazer
authors: Maurizio
authors: M
authors: Pellecchia
authors: John C
authors: JC
authors: Reed
authors: Catriona H M
authors: CH
authors: Jamieson
mesh_terms: D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D006072:Gossypol