PMID- 30373751
OWN - NLM
STAT- MEDLINE
DCOM- 20190703
LR  - 20240210
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 25
IP  - 8
DP  - 2019 Apr 15
TI  - Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic 
      Lymphocytic Leukemia Patients.
PG  - 2503-2512
LID - 10.1158/1078-0432.CCR-18-1286 [doi]
AB  - PURPOSE: In chronic lymphocytic leukemia (CLL), disease progression associates 
      with surface IgM (sIgM) levels and signaling capacity. These are variably 
      downmodulated in vivo and recover in vitro, suggesting a reversible influence of 
      tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an 
      inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell 
      redistribution into the blood, with significant clinical benefit. Circulating CLL 
      cells persist in an inhibited state, offering a tool to investigate the effects 
      of drug on BTK-inhibited sIgM. EXPERIMENTAL DESIGN: We investigated the 
      consequences of ibrutinib therapy on levels and function of sIgM in circulating 
      leukemic cells of patients with CLL. RESULTS: At week 1, there was a significant 
      increase of sIgM expression (64% increase from pretherapy) on CLL cells either 
      recently released from tissue or persisting in blood. In contrast, surface IgD 
      (sIgD) and a range of other receptors did not change. SIgM levels remained higher 
      than pretherapy in the following 3 months despite gradual cell size reduction and 
      ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did 
      not increase and gradually declined. Recovered sIgM was fully N-glycosylated, 
      another feature of escape from antigen, and expression did not increase further 
      during culture in vitro. The sIgM was fully capable of mediating phosphorylation 
      of SYK, which lies upstream of BTK in the B-cell receptor pathway. CONCLUSIONS: 
      This specific IgM increase in patients underpins the key role of tissue-based 
      engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and 
      reveals dynamic adaptability of CLL cells to precision monotherapy.See related 
      commentary by Burger, p. 2372.
CI  - (c)2018 American Association for Cancer Research.
FAU - Drennan, Samantha
AU  - Drennan S
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Chiodin, Giorgia
AU  - Chiodin G
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - D'Avola, Annalisa
AU  - D'Avola A
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Tracy, Ian
AU  - Tracy I
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Johnson, Peter W
AU  - Johnson PW
AUID- ORCID: 0000-0003-2306-4974
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Trentin, Livio
AU  - Trentin L
AUID- ORCID: 0000-0003-1222-6149
AD  - Padua University School of Medicine, Department of Medicine, Hematology and 
      Clinical Immunology Branch, Padua, Italy.
FAU - Steele, Andrew J
AU  - Steele AJ
AUID- ORCID: 0000-0003-0667-1596
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Packham, Graham
AU  - Packham G
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Stevenson, Freda K
AU  - Stevenson FK
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom.
FAU - Forconi, Francesco
AU  - Forconi F
AUID- ORCID: 0000-0002-2211-1831
AD  - Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine 
      Centres, University of Southampton, Southampton, United Kingdom. 
      f.forconi@soton.ac.uk.
AD  - Haematology Department, Cancer Care Directorate, University Hospital Southampton 
      NHS Trust, Southampton, United Kingdom.
LA  - eng
GR  - 18009/LLR_/Blood Cancer UK/United Kingdom
GR  - 23669/CRUK_/Cancer Research UK/United Kingdom
GR  - 14037/LLR_/Blood Cancer UK/United Kingdom
GR  - 16003/LLR_/Blood Cancer UK/United Kingdom
GR  - 12021/LLR_/Blood Cancer UK/United Kingdom
PT  - Journal Article
DEP - 20181029
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Immunoglobulin M)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 1X70OSD4VX (ibrutinib)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - JAC85A2161 (Adenine)
SB  - IM
CIN - Clin Cancer Res. 2019 Apr 15;25(8):2372-2374. PMID: 30728153
MH  - Adenine/analogs & derivatives
MH  - Humans
MH  - Immunoglobulin M
MH  - *Leukemia, Lymphocytic, Chronic, B-Cell
MH  - Piperidines
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Pyrazoles
MH  - Pyrimidines
EDAT- 2018/10/31 06:00
MHDA- 2019/07/04 06:00
CRDT- 2018/10/31 06:00
PHST- 2018/04/25 00:00 [received]
PHST- 2018/07/26 00:00 [revised]
PHST- 2018/10/25 00:00 [accepted]
PHST- 2018/10/31 06:00 [pubmed]
PHST- 2019/07/04 06:00 [medline]
PHST- 2018/10/31 06:00 [entrez]
AID - 1078-0432.CCR-18-1286 [pii]
AID - 10.1158/1078-0432.CCR-18-1286 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2019 Apr 15;25(8):2503-2512. doi: 10.1158/1078-0432.CCR-18-1286. 
      Epub 2018 Oct 29.