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.

A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition / 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. Morris;Karen Messer;Lawrence S.B. Goldstein;Thomas J. Hudson;Marco Marra;Kelly A. Frazer;Maurizio Pellecchia;John C. Reed;Catriona H.M. Jamieson. - In: CELL STEM CELL. - ISSN 1934-5909. - STAMPA. - 12:(2013), pp. 316-328. [10.1016/j.stem.2012.12.011]

A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition

MARTINELLI, GIOVANNI;
2013

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.
2013
A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition / 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. Morris;Karen Messer;Lawrence S.B. Goldstein;Thomas J. Hudson;Marco Marra;Kelly A. Frazer;Maurizio Pellecchia;John C. Reed;Catriona H.M. Jamieson. - In: CELL STEM CELL. - ISSN 1934-5909. - STAMPA. - 12:(2013), pp. 316-328. [10.1016/j.stem.2012.12.011]
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. Morris;Karen Messer;Lawrence S.B. Goldstein;Thomas J. Hudson;Marco Marra;Kelly A. Frazer;Maurizio Pellecchia;John C. Reed;Catriona H.M. Jamieson
File in questo prodotto:
Eventuali allegati, non sono esposti

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/393833
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 94
  • Scopus 159
  • ???jsp.display-item.citation.isi??? 153
social impact