PMID- 32452017
OWN - NLM
STAT- MEDLINE
DCOM- 20210622
LR  - 20210630
IS  - 1365-2141 (Electronic)
IS  - 0007-1048 (Print)
IS  - 0007-1048 (Linking)
VI  - 192
IP  - 3
DP  - 2021 Feb
TI  - Investigating the response of paediatric leukaemia-propagating cells to BCL-2 
      inhibitors.
PG  - 577-588
LID - 10.1111/bjh.16773 [doi]
AB  - Relapse of paediatric acute lymphoblastic leukaemia (ALL) may occur due to 
      persistence of resistant cells with leukaemia-propagating ability (LPC). In 
      leukaemia, the balance of B-cell lymphoma-2 (BCL-2) family proteins is disrupted, 
      promoting survival of malignant cells and possibly LPC. A direct comparison of 
      BCL-2 inhibitors, navitoclax and venetoclax, was undertaken on LPC subpopulations 
      from B-cell precursor (BCP) and T-cell ALL (T-ALL) cases in vitro and in vivo. 
      Responses were compared to BCL-2 levels detected by microarray analyses and 
      Western blotting. In vitro, both drugs were effective against most BCP-ALL LPC, 
      except CD34(-) /CD19(-) cells. In contrast, only navitoclax was effective in 
      T-ALL and CD34(-) /CD7(-) LPC were resistant to both drugs. In vivo, navitoclax 
      was more effective than venetoclax, significantly improving survival of mice 
      engrafted with BCP- and T-ALL samples. Venetoclax was not particularly effective 
      against T-ALL cases in vivo. The proportions of CD34(+) /CD19(-) , CD34(-) 
      /CD19(-) BCP-ALL cells and CD34(-) /CD7(-) T-ALL cells increased significantly 
      following in vivo treatment. Expression of pro-apoptotic BCL-2 genes was lower in 
      these subpopulations, which may explain the lack of sensitivity. These data 
      demonstrate that some LPC were resistant to BCL-2 inhibitors and sustained 
      remission will require their use in combination with other therapeutics.
CI  - (c) 2020 The Authors. British Journal of Haematology published by British Society 
      for Haematology and John Wiley & Sons Ltd.
FAU - Diamanti, Paraskevi
AU  - Diamanti P
AD  - Bristol Institute for Transfusion Sciences, NHSBT Filton, Bristol, UK.
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
FAU - Ede, Benjamin C
AU  - Ede BC
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
FAU - Dace, Phoebe Ei
AU  - Dace PE
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
FAU - Barendt, William J
AU  - Barendt WJ
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
FAU - Cox, Charlotte V
AU  - Cox CV
AD  - Bristol Institute for Transfusion Sciences, NHSBT Filton, Bristol, UK.
FAU - Hancock, Jeremy P
AU  - Hancock JP
AD  - Bristol Genetics Laboratory, Severn Pathology, North Bristol Trust, Bristol, UK.
FAU - Moppett, John P
AU  - Moppett JP
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
AD  - Bristol Royal Hospital for Children, Bristol, UK.
FAU - Blair, Allison
AU  - Blair A
AUID- ORCID: 0000-0002-9759-5156
AD  - Bristol Institute for Transfusion Sciences, NHSBT Filton, Bristol, UK.
AD  - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
LA  - eng
GR  - RP-PG-0310-1003/Programme Grants for Applied Research/
GR  - National Institute for Health Research/
GR  - NHS Blood and Transplant/
GR  - WT_/Wellcome Trust/United Kingdom
GR  - University of Bristol/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200525
PL  - England
TA  - Br J Haematol
JT  - British journal of haematology
JID - 0372544
RN  - 0 (Aniline Compounds)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Sulfonamides)
RN  - N54AIC43PW (venetoclax)
RN  - XKJ5VVK2WD (navitoclax)
SB  - IM
MH  - Adolescent
MH  - Aniline Compounds/*therapeutic use
MH  - Antineoplastic Agents/*therapeutic use
MH  - Bridged Bicyclo Compounds, Heterocyclic/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Humans
MH  - Male
MH  - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
MH  - Proto-Oncogene Proteins c-bcl-2/analysis/*antagonists & inhibitors
MH  - Sulfonamides/*therapeutic use
MH  - Treatment Outcome
PMC - PMC8237230
OTO - NOTNLM
OT  - ALL
OT  - BCL-2
OT  - LPC
OT  - NSG
OT  - Navitoclax
OT  - Venetoclax
OT  - paediatric ALL
COIS- The authors declare to have no potential conflicts of interest regarding the 
      present work.
EDAT- 2020/05/27 06:00
MHDA- 2021/06/23 06:00
PMCR- 2021/06/28
CRDT- 2020/05/27 06:00
PHST- 2020/01/23 00:00 [received]
PHST- 2020/05/01 00:00 [accepted]
PHST- 2020/05/27 06:00 [pubmed]
PHST- 2021/06/23 06:00 [medline]
PHST- 2020/05/27 06:00 [entrez]
PHST- 2021/06/28 00:00 [pmc-release]
AID - BJH16773 [pii]
AID - 10.1111/bjh.16773 [doi]
PST - ppublish
SO  - Br J Haematol. 2021 Feb;192(3):577-588. doi: 10.1111/bjh.16773. Epub 2020 May 25.