Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Either IL-7 activation of JAK-STAT or BEZ inhibition of PI3K-AKT-mTOR pathways dominates the single-cell phosphosignature of ex vivo treated pediatric T-cell acute lymphoblastic leukemia cells

D. Kuzilková, C. Bugarin, K. Rejlova, AR. Schulz, HE. Mei, M. Paganin, A. Biffi, A. Biondi, T. Kalina, G. Gaipa

. 2022 ; 107 (6) : 1293-1310. [pub] 20220601

Jazyk angličtina Země Itálie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22018172

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from lymphoblasts of T-cell origin. While TALL accounts for only 15% of childhood and 25% of adult ALL, 30% of patients relapse with a poor outcome. Targeted therapy of resistant and high-risk pediatric T-ALL is therefore urgently needed, together with precision medicine tools allowing the testing of efficacy in patient samples. Furthermore, leukemic cell heterogeneity requires drug response assessment at the single-cell level. Here we used single-cell mass cytometry to study signal transduction pathways such as JAK-STAT, PI3K-AKT-mTOR and MEK-ERK in 16 diagnostic and five relapsed T-ALL primary samples, and investigated the in vitro response of cells to Interleukin-7 (IL-7) and the inhibitor BEZ-235. T-ALL cells showed upregulated activity of the PI3K-AKT-mTOR and MEK-ERK pathways and increased expression of proliferation and translation markers. We found that perturbation induced by the ex vivo administration of either IL-7 or BEZ-235 reveals a high degree of exclusivity with respect to the phospho-protein responsiveness to these agents. Notably, these response signatures were maintained from diagnosis to relapse in individual patients. In conclusion, we demonstrated the power of mass cytometry single-cell profiling of signal transduction pathways in T-ALL. Taking advantage of this advanced approach, we were able to identify distinct clusters with different responsiveness to IL-7 and BEZ-235 that can persist at relapse. Collectively our observations can contribute to a better understanding of the complex signaling network governing T-ALL behavior and its correlation with influence on the response to therapy.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22018172
003      
CZ-PrNML
005      
20220804134610.0
007      
ta
008      
220720s2022 it f 000 0|eng||
009      
AR
024    7_
$a 10.3324/haematol.2021.278796 $2 doi
035    __
$a (PubMed)34670357
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a it
100    1_
$a Kuzilková, Daniela $u Childhood Leukaemia Investigation Prague, Czech Republic; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Czech Republic
245    10
$a Either IL-7 activation of JAK-STAT or BEZ inhibition of PI3K-AKT-mTOR pathways dominates the single-cell phosphosignature of ex vivo treated pediatric T-cell acute lymphoblastic leukemia cells / $c D. Kuzilková, C. Bugarin, K. Rejlova, AR. Schulz, HE. Mei, M. Paganin, A. Biffi, A. Biondi, T. Kalina, G. Gaipa
520    9_
$a T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from lymphoblasts of T-cell origin. While TALL accounts for only 15% of childhood and 25% of adult ALL, 30% of patients relapse with a poor outcome. Targeted therapy of resistant and high-risk pediatric T-ALL is therefore urgently needed, together with precision medicine tools allowing the testing of efficacy in patient samples. Furthermore, leukemic cell heterogeneity requires drug response assessment at the single-cell level. Here we used single-cell mass cytometry to study signal transduction pathways such as JAK-STAT, PI3K-AKT-mTOR and MEK-ERK in 16 diagnostic and five relapsed T-ALL primary samples, and investigated the in vitro response of cells to Interleukin-7 (IL-7) and the inhibitor BEZ-235. T-ALL cells showed upregulated activity of the PI3K-AKT-mTOR and MEK-ERK pathways and increased expression of proliferation and translation markers. We found that perturbation induced by the ex vivo administration of either IL-7 or BEZ-235 reveals a high degree of exclusivity with respect to the phospho-protein responsiveness to these agents. Notably, these response signatures were maintained from diagnosis to relapse in individual patients. In conclusion, we demonstrated the power of mass cytometry single-cell profiling of signal transduction pathways in T-ALL. Taking advantage of this advanced approach, we were able to identify distinct clusters with different responsiveness to IL-7 and BEZ-235 that can persist at relapse. Collectively our observations can contribute to a better understanding of the complex signaling network governing T-ALL behavior and its correlation with influence on the response to therapy.
650    _2
$a dítě $7 D002648
650    _2
$a lidé $7 D006801
650    12
$a interleukin-7 $x farmakologie $7 D015851
650    _2
$a fosfatidylinositol-3-kinasy $x metabolismus $7 D019869
650    12
$a lymfoblastická leukemie-lymfom z prekurzorových T-buněk $x farmakoterapie $x metabolismus $7 D054218
650    _2
$a protoonkogenní proteiny c-akt $x metabolismus $7 D051057
650    _2
$a recidiva $7 D012008
650    _2
$a T-lymfocyty $x metabolismus $7 D013601
650    _2
$a TOR serin-threoninkinasy $x metabolismus $7 D058570
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Bugarin, Cristina $u Fondazione Tettamanti, Clinica Pediatrica Università degli Studi Milano Bicocca, Monza (MB), Italy
700    1_
$a Rejlova, Katerina $u Childhood Leukaemia Investigation Prague, Czech Republic; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Czech Republic
700    1_
$a Schulz, Axel R $u German Rheumatism Research Center Berlin (DRFZ), a Leibniz Institute, Berlin, Germany
700    1_
$a Mei, Henrik E $u German Rheumatism Research Center Berlin (DRFZ), a Leibniz Institute, Berlin, Germany
700    1_
$a Paganin, Maddalena $u Pediatric Hematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, University of Padova, Padova, Italy
700    1_
$a Biffi, Alessandra $u Pediatric Hematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, University of Padova, Padova, Italy
700    1_
$a Biondi, Andrea $u Fondazione Tettamanti, Clinica Pediatrica Università degli Studi Milano Bicocca, Monza (MB), Italy. andrea.biondi@unimib.it
700    1_
$a Kalina, Tomas $u Childhood Leukaemia Investigation Prague, Czech Republic; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Czech Republic
700    1_
$a Gaipa, Giuseppe $u Fondazione Tettamanti, Clinica Pediatrica Università degli Studi Milano Bicocca, Monza (MB), Italy
773    0_
$w MED00001963 $t Haematologica $x 1592-8721 $g Roč. 107, č. 6 (2022), s. 1293-1310
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34670357 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220720 $b ABA008
991    __
$a 20220804134604 $b ABA008
999    __
$a ok $b bmc $g 1821980 $s 1169415
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 107 $c 6 $d 1293-1310 $e 20220601 $i 1592-8721 $m Haematologica $n Haematologica $x MED00001963
LZP    __
$a Pubmed-20220720

Najít záznam

Citační ukazatele

Možnosti archivace