PMID- 36982791
OWN - NLM
STAT- MEDLINE
DCOM- 20230330
LR  - 20230331
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 6
DP  - 2023 Mar 16
TI  - Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the 
      Molecular Mechanisms of AML Treatments Using Phosphoproteomics.
LID - 10.3390/ijms24065717 [doi]
LID - 5717
AB  - Paediatric acute myeloid leukaemia (AML) continues to present treatment 
      challenges, as no "standard approach" exists to treat those young patients 
      reliably and safely. Combination therapies could become a viable treatment option 
      for treating young patients with AML, allowing multiple pathways to be targeted. 
      Our in silico analysis of AML patients highlighted "cell death and survival" as 
      an aberrant, potentially targetable pathway in paediatric AML patients. 
      Therefore, we aimed to identify novel combination therapies to target apoptosis. 
      Our apoptotic drug screening resulted in the identification of one potential 
      "novel" drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the 
      CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT 
      inhibitor + SU9516, which showed significant synergism in a series of paediatric 
      AML cell lines. Using a phosphoproteomic approach to understand the apoptotic 
      mechanism involved, proteins related to apoptotic cell death and cell survival 
      were represented, in agreement with further results showing differentially 
      expressed apoptotic proteins and their phosphorylated forms among combination 
      treatments compared to single-agent treated cells such upregulation of BAX and 
      its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and 
      downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total 
      levels of Bcl-2 were decreased but correlated with increased levels of 
      phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis 
      predictions. Bcl-2 phosphorylation was regulated by 
      extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although 
      the mechanism linking to Bcl-2 phosphorylation remains to be determined, our 
      findings provide first-hand insights on potential novel combination treatments 
      for AML.
FAU - Ali, Ahlam A
AU  - Ali AA
AD  - Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, 
      Dentistry and Biomedical Sciences, Queens University Belfast, Belfast BT9 7AE, 
      Northern Ireland, UK.
FAU - Cairns, Lauren V
AU  - Cairns LV
AD  - Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 
      Belfast BT9 7AE, Northern Ireland, UK.
FAU - Clarke, Kathryn M
AU  - Clarke KM
AD  - Haematology Department, C-Floor Tower Block, Belfast City Hospital, Belfast BT9 
      7AB, Northern Ireland, UK.
FAU - Blayney, Jaine K
AU  - Blayney JK
AD  - Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 
      Belfast BT9 7AE, Northern Ireland, UK.
FAU - Lappin, Katrina M
AU  - Lappin KM
AUID- ORCID: 0000-0002-6463-5430
AD  - Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 
      Belfast BT9 7AE, Northern Ireland, UK.
FAU - Mills, Ken I
AU  - Mills KI
AUID- ORCID: 0000-0002-6362-4481
AD  - Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 
      Belfast BT9 7AE, Northern Ireland, UK.
LA  - eng
GR  - CCLGA 2019 01/Children's Cancer and Leukaemia Group/
PT  - Journal Article
DEP - 20230316
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (ABT-737)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
SB  - IM
MH  - Child
MH  - Humans
MH  - Cell Line, Tumor
MH  - Myeloid Cell Leukemia Sequence 1 Protein/metabolism
MH  - *Leukemia, Myeloid, Acute/drug therapy/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Apoptosis
PMC - PMC10058112
OTO - NOTNLM
OT  - AML
OT  - apoptosis
OT  - double combination
OT  - drug screening
OT  - paediatric
OT  - phosphoproteomics
OT  - synergism
OT  - triple combination
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2023/03/30 06:00
MHDA- 2023/03/30 06:11
PMCR- 2023/03/16
CRDT- 2023/03/29 01:39
PHST- 2023/01/26 00:00 [received]
PHST- 2023/03/03 00:00 [revised]
PHST- 2023/03/08 00:00 [accepted]
PHST- 2023/03/30 06:11 [medline]
PHST- 2023/03/29 01:39 [entrez]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/16 00:00 [pmc-release]
AID - ijms24065717 [pii]
AID - ijms-24-05717 [pii]
AID - 10.3390/ijms24065717 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Mar 16;24(6):5717. doi: 10.3390/ijms24065717.