PMID- 32581241
OWN - NLM
STAT- MEDLINE
DCOM- 20200826
LR  - 20210624
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 11
IP  - 1
DP  - 2020 Jun 24
TI  - Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in 
      Philadelphia chromosome-positive acute lymphoblastic leukemia.
PG  - 3194
LID - 10.1038/s41467-020-16927-w [doi]
LID - 3194
AB  - Ph(+) acute lymphoblastic leukemia (ALL) is characterized by the expression of an 
      oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 
      receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 
      and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors 
      results in elevated expression of IL7R which enables the survival of transformed 
      cells when IL7 was added together with the kinase inhibitors. Importantly, 
      treatment with anti-IL7R antibodies prevents leukemia development in 
      xenotransplantation models using patient-derived Ph(+) ALL cells. Our results 
      suggest that the association between IL7R and CXCR4 serves as molecular platform 
      for BCR-ABL1-induced transformation and development of Ph(+) ALL. Targeting this 
      platform with anti-IL7R antibody eliminates Ph(+) ALL cells including those with 
      resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies 
      may provide alternative treatment options for ALL in general and may suppress 
      incurable drug-resistant leukemia forms.
FAU - Abdelrasoul, Hend
AU  - Abdelrasoul H
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Vadakumchery, Anila
AU  - Vadakumchery A
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Werner, Markus
AU  - Werner M
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Lenk, Lennart
AU  - Lenk L
AD  - Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University 
      Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
FAU - Khadour, Ahmad
AU  - Khadour A
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Young, Marc
AU  - Young M
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - El Ayoubi, Omar
AU  - El Ayoubi O
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Vogiatzi, Fotini
AU  - Vogiatzi F
AD  - Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University 
      Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
FAU - Kramer, Markus
AU  - Kramer M
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Schmid, Vera
AU  - Schmid V
AUID- ORCID: 0000-0002-6035-2265
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Chen, Zhengshan
AU  - Chen Z
AD  - Department of Systems Biology and City of Hope Comprehensive Cancer Center, 
      Monrovia, CA, USA.
FAU - Yousafzai, Yasar
AU  - Yousafzai Y
AD  - Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Cario, Gunnar
AU  - Cario G
AD  - Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University 
      Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
FAU - Schrappe, Martin
AU  - Schrappe M
AD  - Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University 
      Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
FAU - Muschen, Markus
AU  - Muschen M
AUID- ORCID: 0000-0002-6064-8613
AD  - Department of Systems Biology and City of Hope Comprehensive Cancer Center, 
      Monrovia, CA, USA.
FAU - Halsey, Christina
AU  - Halsey C
AUID- ORCID: 0000-0001-5449-5246
AD  - Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Mulaw, Medhanie A
AU  - Mulaw MA
AUID- ORCID: 0000-0002-2501-6952
AD  - Institute of Experimental Cancer Research, Medical Faculty, University of Ulm, 
      Ulm, Germany.
FAU - Schewe, Denis M
AU  - Schewe DM
AUID- ORCID: 0000-0002-1070-0217
AD  - Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University 
      Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
FAU - Hobeika, Elias
AU  - Hobeika E
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Alsadeq, Ameera
AU  - Alsadeq A
AUID- ORCID: 0000-0003-0568-9890
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
FAU - Jumaa, Hassan
AU  - Jumaa H
AUID- ORCID: 0000-0003-3383-141X
AD  - Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany. 
      hassan.jumaa@uni-ulm.de.
LA  - eng
GR  - R01 CA213138/CA/NCI NIH HHS/United States
GR  - R01 CA157644/CA/NCI NIH HHS/United States
GR  - R35 CA197628/CA/NCI NIH HHS/United States
GR  - ETM/374/CSO_/Chief Scientist Office/United Kingdom
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200624
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (CXCR4 protein, human)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (IL7R protein, human)
RN  - 0 (Interleukin-7)
RN  - 0 (Interleukin-7 Receptor alpha Subunit)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, CXCR4)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Transformation, Neoplastic/drug effects
MH  - Female
MH  - Forkhead Box Protein O1/metabolism
MH  - Fusion Proteins, bcr-abl/antagonists & inhibitors/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Interleukin-7/pharmacology
MH  - Interleukin-7 Receptor alpha Subunit/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - *Philadelphia Chromosome
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism/*pathology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Receptors, CXCR4/genetics/*metabolism
MH  - Signal Transduction/drug effects
PMC - PMC7314847
COIS- The authors declare no competing interests.
EDAT- 2020/06/26 06:00
MHDA- 2020/08/28 06:00
PMCR- 2020/06/24
CRDT- 2020/06/26 06:00
PHST- 2019/08/08 00:00 [received]
PHST- 2020/05/29 00:00 [accepted]
PHST- 2020/06/26 06:00 [entrez]
PHST- 2020/06/26 06:00 [pubmed]
PHST- 2020/08/28 06:00 [medline]
PHST- 2020/06/24 00:00 [pmc-release]
AID - 10.1038/s41467-020-16927-w [pii]
AID - 16927 [pii]
AID - 10.1038/s41467-020-16927-w [doi]
PST - epublish
SO  - Nat Commun. 2020 Jun 24;11(1):3194. doi: 10.1038/s41467-020-16927-w.