The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system.
Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central nervous system positivity in T-cell acute lymphoblastic leukemia (odds ratio=11.00, 95% confidence interval, 2.00-60.62). We propose zeta-chain-associated protein kinase 70, CCR7 and CXCR4 as markers of central nervous system infiltration in acute lymphoblastic leukemia warranting prospective investigation.
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Ameera
A
Alsadeq
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Henning
H
Fedders
Kiel Pediatric Tumor Registry, Department of Pediatric Pathology, University Medical Center Schleswig-Holstein, Germany.
Christian
C
Vokuhl
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Nele M
NM
Belau
Pediatric Hematology and Oncology, Hannover Medical School, Germany.
Martin
M
Zimmermann
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Tim
T
Wirbelauer
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Steffi
S
Spielberg
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Michaela
M
Vossen-Gajcy
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Gunnar
G
Cario
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Martin
M
Schrappe
Department of General Pediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany denis.schewe@uksh.de.
Denis M
DM
Schewe
D000818:Animals; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D017254:Leukemic Infiltration / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*
D054398:Receptors, CCR4; D054400:Receptors, CCR7; D051746:ZAP-70 Protein-Tyrosine Kinase; D048049:Extracellular Signal-Regulated MAP Kinases
Oncotarget. 2016 Jan 19;7(3):2809-22
26646452
Lancet Oncol. 2008 Mar;9(3):257-68
18308251
Nature. 2009 Jun 18;459(7249):1000-4
19536265
J Biol Chem. 2010 Dec 10;285(50):38781-7
20889506
Cancer. 1973 Mar;31(3):520-33
4511909
Lancet. 1981 Nov 14;2(8255):1115
6118564
JAMA. 2002 Oct 23-30;288(16):2001-7
12387652
Blood. 2011 Sep 15;118(11):3080-7
21680795
Haematologica. 2012 Nov;97(11):1743-50
22580999
PLoS One. 2013 Dec 03;8(12):e81221
24312539
Blood. 2015 Jan 29;125(5):820-30
25428221
Blood. 2010 Nov 4;116(18):3409-17
20656928
Cancer Immunol Immunother. 2015 Jun;64(6):665-76
25724841
Cancer Cell. 2015 Mar 9;27(3):409-25
25759025
J Leukoc Biol. 2006 Jun;79(6):1157-65
16603585
Leukemia. 2015 Dec;29(12):2307-16
26104660
Blood. 2016 Apr 21;127(16):1998-2006
26869395
Cell Cycle. 2010 Apr 15;9(8):1629-38
20372086
Nat Methods. 2012 Jul;9(7):671-5
22930834
EMBO J. 2008 May 7;27(9):1333-44
18369315
Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3625-34
14506150
J Immunol. 2001 Aug 15;167(4):1857-61
11489961
Leuk Lymphoma. 2004 Dec;45(12):2491-6
15621766
JAMA. 1971 Apr 26;216(4):648-52
5279904
Cold Spring Harb Perspect Biol. 2010 May;2(5):a002279
20452964
Mol Cytogenet. 2012 May 01;5(1):22
22548957
Int J Lab Hematol. 2008 Apr;30(2):149-57
18333847
J Clin Oncol. 2003 May 1;21(9):1798-809
12721257
Br J Haematol. 2008 Mar;140(6):665-72
18241254
Blood. 2011 Oct 20;118(16):4401-10
21865343
N Engl J Med. 2004 Aug 26;351(9):893-901
15329427
Blood. 2002 May 1;99(9):3111-8
11964272
Blood. 2006 Jan 1;107(1):197-204
16160012
Blood. 2005 Mar 1;105(5):2036-41
15514014
Blood Cells Mol Dis. 2015 Oct;55(3):220-7
26227851
Leukemia. 2000 Dec;14(12):2247-56
11187916
J Leukoc Biol. 2016 Jun;99(6):1077-87
26931577
N Engl J Med. 2006 Jan 12;354(2):166-78
16407512
Blood. 2000 Nov 15;96(10):3381-4
11071631
Science. 2008 Dec 19;322(5909):1861-5
19095944
Ann Hematol. 2002 Jul;81(7):402-4
12185514
Blood. 2007 Mar 1;109 (5):2032-9
17038529
Cancer Cell. 2015 Jul 13;28(1):114-28
26073130
Leukemia. 2009 Aug;23(8):1406-9
19282835
Immunol Rev. 2009 Mar;228(1):41-57
19290920
Blood. 2014 Nov 27;124(23):3420-30
25253770
Blood. 2002 Dec 15;100(13):4609-14
12393534
J Clin Oncol. 2003 Jan 15;21(2):184-8
12525508
J Clin Invest. 2014 Mar;124(3):1228-41
24569378