PMID- 28576876
OWN - NLM
STAT- MEDLINE
DCOM- 20170810
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 130
IP  - 5
DP  - 2017 Aug 3
TI  - Targeting chronic myeloid leukemia stem cells with the hypoxia-inducible factor 
      inhibitor acriflavine.
PG  - 655-665
LID - 10.1182/blood-2016-10-745588 [doi]
AB  - Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC)-driven 
      neoplasia characterized by expression of the constitutively active tyrosine 
      kinase BCR/Abl. CML therapy based on tyrosine kinase inhibitors (TKIs) is highly 
      effective in inducing remission but not in targeting leukemia stem cells (LSCs), 
      which sustain minimal residual disease and are responsible for CML relapse 
      following discontinuation of treatment. The identification of molecules capable 
      of targeting LSCs appears therefore of primary importance to aim at CML 
      eradication. LSCs home in bone marrow areas at low oxygen tension, where HSCs are 
      physiologically hosted. This study addresses the effects of pharmacological 
      inhibition of hypoxia-inducible factor-1 (HIF-1), a critical regulator of LSC 
      survival, on the maintenance of CML stem cell potential. We found that the HIF-1 
      inhibitor acriflavine (ACF) decreased survival and growth of CML cells. These 
      effects were paralleled by decreased expression of c-Myc and stemness-related 
      genes. Using different in vitro stem cell assays, we showed that ACF, but not 
      TKIs, targets the stem cell potential of CML cells, including primary cells 
      explanted from 12 CML patients. Moreover, in a murine CML model, ACF decreased 
      leukemia development and reduced LSC maintenance. Importantly, ACF exhibited 
      significantly less-severe effects on non-CML hematopoietic cells in vitro and in 
      vivo. Thus, we propose ACF, a US Food and Drug Administration (FDA)-approved drug 
      for nononcological use in humans, as a novel therapeutic approach to prevent CML 
      relapse and, in combination with TKIs, enhance induction of remission.
CI  - (c) 2017 by The American Society of Hematology.
FAU - Cheloni, Giulia
AU  - Cheloni G
AUID- ORCID: 0000-0002-7682-3826
AD  - Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", 
      Universita degli Studi di Firenze, Florence, Italy.
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA.
AD  - Istituto Toscano Tumori, Tuscany, Italy.
FAU - Tanturli, Michele
AU  - Tanturli M
AUID- ORCID: 0000-0002-2642-1706
AD  - Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", 
      Universita degli Studi di Firenze, Florence, Italy.
FAU - Tusa, Ignazia
AU  - Tusa I
AD  - Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", 
      Universita degli Studi di Firenze, Florence, Italy.
AD  - Istituto Toscano Tumori, Tuscany, Italy.
FAU - Ho DeSouza, Ngoc
AU  - Ho DeSouza N
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA.
FAU - Shan, Yi
AU  - Shan Y
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA.
FAU - Gozzini, Antonella
AU  - Gozzini A
AD  - Unita Funzionale di Ematologia, Azienda Ospedaliero-Universitaria Careggi (AOUC), 
      Florence, Italy; and.
FAU - Mazurier, Frederic
AU  - Mazurier F
AUID- ORCID: 0000-0002-6984-7096
AD  - Equipe Niche Leucemique et Metabolisme Oxydatif, Genetique, Immunotherapie, 
      Chimie et Cancer, Unite Mixte de Recherche 7292, Centre National de la Recherche 
      Scientifique, Universite Francois-Rabelais de Tours, Tours, France.
FAU - Rovida, Elisabetta
AU  - Rovida E
AUID- ORCID: 0000-0002-5949-3239
AD  - Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", 
      Universita degli Studi di Firenze, Florence, Italy.
AD  - Istituto Toscano Tumori, Tuscany, Italy.
FAU - Li, Shaoguang
AU  - Li S
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA.
FAU - Dello Sbarba, Persio
AU  - Dello Sbarba P
AUID- ORCID: 0000-0001-6411-569X
AD  - Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", 
      Universita degli Studi di Firenze, Florence, Italy.
AD  - Istituto Toscano Tumori, Tuscany, Italy.
LA  - eng
GR  - R01 CA176179/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170602
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Neoplasm Proteins)
RN  - 1T3A50395T (Acriflavine)
SB  - IM
MH  - Acriflavine/*pharmacology
MH  - Animals
MH  - Cell Survival
MH  - Drug Delivery Systems/*methods
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors/metabolism
MH  - K562 Cells
MH  - *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug 
      therapy/metabolism/pathology
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Neoplasm Proteins/*antagonists & inhibitors/metabolism
MH  - *Neoplasms, Experimental/drug therapy/metabolism/pathology
MH  - Neoplastic Stem Cells/*metabolism/pathology
PMC - PMC5942867
COIS- Conflict-of-interest disclosure: The authors declare no competing financial 
      interests.
EDAT- 2017/06/04 06:00
MHDA- 2017/08/11 06:00
PMCR- 2017/08/03
CRDT- 2017/06/04 06:00
PHST- 2016/10/14 00:00 [received]
PHST- 2017/05/22 00:00 [accepted]
PHST- 2017/06/04 06:00 [pubmed]
PHST- 2017/08/11 06:00 [medline]
PHST- 2017/06/04 06:00 [entrez]
PHST- 2017/08/03 00:00 [pmc-release]
AID - S0006-4971(20)33137-2 [pii]
AID - 2016/745588 [pii]
AID - 10.1182/blood-2016-10-745588 [doi]
PST - ppublish
SO  - Blood. 2017 Aug 3;130(5):655-665. doi: 10.1182/blood-2016-10-745588. Epub 2017 
      Jun 2.