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Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
- MeSH
- anaplastická lymfomová kináza antagonisté a inhibitory metabolismus MeSH
- anaplastický velkobuněčný lymfom farmakoterapie metabolismus MeSH
- inhibitory proteinkinas farmakologie MeSH
- krizotinib farmakologie MeSH
- lidé MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- nádorové buněčné linie MeSH
- protinádorové látky farmakologie MeSH
- tyrosinfosfatasa nereceptorového typu 1 metabolismus MeSH
- tyrosinfosfatasa nereceptorového typu 2 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
APMIS, ISSN 0903-465X Supplement Vol. 105. 73
28 s. : il. ; 28 cm
Ze tkáně placenty byly po fixaci 10% formolem připraveny z parafínových bločků řezy, v nichž byly imunohistochemicky ' byly imunohistochemicky buď nepřímou imunoperoxidázovou metodou ve dvou vrstvách, nebo s užitím biotin-strepavidinového komplexu značeného alkalifosfatázou prokazovány krevní skupinové substance A, B, H. Je důležité při vyšetření zastihnout jak plodovou, tak i mateřskou část placenty, jejichž skupinové vlastnosti lze identifikovat. Imunohistochemicky průkaz krevních skupinových substancí A, B, H ve tkáni placenty pak dovoluje usuzovat na krevní skupinovou vlastnost nejen plodu, ale i matky.
Blood group substances A, B, H were detect in placental tissue paraffin cuts (after 10% formaline fixation) by immunohistochemistry using indirect immunoperoxidase-two-layers technology or biotin-streptavidin complex signed by alkaline phosphatase. Both fetal and maternal part of placenta are to be investigated which enables their group markers to be identified. Immunohistochemical detection of the A, B, H blood group substances in placenta can give conelusion about the blood group of fetus and of mother as well.
