GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Cancer Cell
Borhane GuezguezMickie Bhatia

Abstract

Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3β dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3β deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3β and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3β provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3α- and GSK-3β-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution.

References

Jun 19, 2002·Blood·Scott C KoganUNKNOWN Hematopathology subcommittee of the Mouse Models of Human Cancers Consortium
Sep 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Emmanuelle PasseguéIrving L Weissman
Apr 16, 2004·The New England Journal of Medicine·Peter J M ValkRuud Delwel
Nov 20, 2004·Blood·Christian RécherBernard Payrastre
Dec 13, 2005·Nature Medicine·Jennifer J TrowbridgeMickie Bhatia
Dec 29, 2005·The Journal of Experimental Medicine·Deepta BhattacharyaIrving L Weissman
Jan 26, 2007·Nature Reviews. Cancer·Seth J CoreyAaron D Schimmer
Oct 2, 2007·Current Opinion in Biotechnology·Dagmar WirthHansjörg Hauser
Jan 18, 2008·Cancer Research·David J WongHoward Y Chang
Nov 22, 2008·Cold Spring Harbor Symposia on Quantitative Biology·M P ChaoI L Weissman
Dec 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Boyi GanRonald A DePinho
Mar 11, 2009·Frontiers in Bioscience (Landmark Edition)·Akihiko Wada
Nov 4, 2009·Trends in Biochemical Sciences·Dianqing Wu, Weijun Pan
Dec 5, 2009·The Journal of Clinical Investigation·Jian HuangPeter S Klein
Mar 9, 2010·Cell Stem Cell·Grant A ChallenMargaret A Goodell
Jul 24, 2010·Annals of the New York Academy of Sciences·You-Mie KimGyesoon Yoon
Sep 10, 2010·The New England Journal of Medicine·Ramin TehranchiSten Eirik W Jacobsen
Dec 15, 2010·Nature Reviews. Clinical Oncology·Naoko TakebeS Percy Ivy
Jan 18, 2011·Hematology·Guillermo Garcia-Manero
Mar 19, 2011·Leukemia·M J WalterT A Graubert
May 11, 2011·British Journal of Haematology·Henrik Hasle, Charlotte M Niemeyer
Jun 15, 2011·Leukemia & Lymphoma·Erica D Warlick, Jeffrey S Miller
Aug 11, 2011·Development·Emma R AnderssonUrban Lendahl
Aug 30, 2011·Nature Medicine·Kolja EppertJohn E Dick
Feb 15, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Julie SchanzDetlef Haase
May 23, 2012·American Journal of Hematology·Sameer A Parikh, Ayalew Tefferi
Jun 12, 2012·Cell·Hans Clevers, Roel Nusse

❮ Previous
Next ❯

Citations

Mar 29, 2016·European Journal of Medicinal Chemistry·Aziz OuachSylvain Routier
Aug 30, 2016·Cancers·Frank J T StaalKarin Pike-Overzet
May 10, 2017·PloS One·Michelle Nguyen-McCarty, Peter S Klein
Aug 18, 2018·Wiley Interdisciplinary Reviews. RNA·Xiaolei Liu, Peter S Klein
Jan 10, 2018·Development·Delong MengJenna L Jewell
Nov 6, 2018·Blood Advances·James J Ignatz-HooverDavid N Wald
Dec 31, 2019·The Journal of Experimental Medicine·Yoon-A KangEmmanuelle Passegué
May 6, 2020·Cells·Przemysław DudaJames A McCubrey
Jun 24, 2020·Journal of Leukocyte Biology·Sheila C Soares-LimaFlávia R G Carneiro
May 16, 2017·Current Stem Cell Reports·Dheeraj Bhavanasi, Peter S Klein
Mar 8, 2019·Cancer Science·Yoshihiro HayashiGang Huang
Mar 4, 2020·FASEB BioAdvances·Noriko YokoyamaKazuhisa Iwabuchi
Nov 11, 2019·Cells·Alicja M GruszkaMyriam Alcalay
Jun 7, 2019·Cancers·Whitney N GoldsberryRebecca C Arend
Oct 19, 2019·Molecular Aspects of Medicine·Nithya MudgapalliKishore B Challagundla
Dec 20, 2020·Biomolecules·Octavio Silva-GarcíaVíctor M Baizabal-Aguirre
Dec 31, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Camilla EvangelistiAlberto M Martelli
Apr 4, 2021·Leukemia·Alberto M MartelliJames A McCubrey
Jun 14, 2020·Blood Reviews·Christine Bellanné-ChantelotIsabelle Plo

❮ Previous
Next ❯

Related Concepts

Related Feeds

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.