PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers

Signal transducer and activator of transcription 5 (STAT5) signaling plays a pathogenic role in both hematologic malignancies and solid tumors. In acute myeloid leukemia (AML), internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD) constitutively activate the FLT3 receptor, producing...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Anna J. Dellomo, Rachel Abbotts, Christian L. Eberly, Mariusz Karbowski, Maria R. Baer, Tami J. Kingsbury, Feyruz V. Rassool
Formato: article
Lenguaje:EN
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://doaj.org/article/1a37956d049b40a797eb0d03b6d03d1b
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:1a37956d049b40a797eb0d03b6d03d1b
record_format dspace
spelling oai:doaj.org-article:1a37956d049b40a797eb0d03b6d03d1b2021-11-22T04:20:16ZPARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers1936-523310.1016/j.tranon.2021.101283https://doaj.org/article/1a37956d049b40a797eb0d03b6d03d1b2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002746https://doaj.org/toc/1936-5233Signal transducer and activator of transcription 5 (STAT5) signaling plays a pathogenic role in both hematologic malignancies and solid tumors. In acute myeloid leukemia (AML), internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD) constitutively activate the FLT3 receptor, producing aberrant STAT5 signaling, driving cell survival and proliferation. Understanding STAT5 regulation may aid development of new treatment strategies in STAT5-activated cancers including FLT3-ITD AML. Poly ADP-ribose polymerase (PARP1), upregulated in FLT3-ITD AML, is primarily known as a DNA repair factor, but also regulates a diverse range of proteins through PARylation. Analysis of STAT5 protein sequence revealed putative PARylation sites and we demonstrate a novel PARP1 interaction and direct PARylation of STAT5 in FLT3-ITD AML. Moreover, PARP1 depletion and PARylation inhibition decreased STAT5 protein expression and activity via increased degradation, suggesting that PARP1 PARylation of STAT5 at least in part potentiates aberrant signaling by stabilizing STAT5 protein in FLT3-ITD AML. Importantly for translational significance, PARPis are cytotoxic in numerous STAT5-activated cancer cells and are synergistic with tyrosine kinase inhibitors (TKI) in both TKI-sensitive and TKI-resistant FLT3-ITD AML. Therefore, PARPi may have therapeutic benefit in STAT5-activated and therapy-resistant leukemias and solid tumors.Anna J. DellomoRachel AbbottsChristian L. EberlyMariusz KarbowskiMaria R. BaerTami J. KingsburyFeyruz V. RassoolElsevierarticleSTAT5 protein stabilityPost-translational modificationsPARYlationPARP inhibitionTKI-resistant FLT3-ITD AMLNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101283- (2022)
institution DOAJ
collection DOAJ
language EN
topic STAT5 protein stability
Post-translational modifications
PARYlation
PARP inhibition
TKI-resistant FLT3-ITD AML
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
spellingShingle STAT5 protein stability
Post-translational modifications
PARYlation
PARP inhibition
TKI-resistant FLT3-ITD AML
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Anna J. Dellomo
Rachel Abbotts
Christian L. Eberly
Mariusz Karbowski
Maria R. Baer
Tami J. Kingsbury
Feyruz V. Rassool
PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
description Signal transducer and activator of transcription 5 (STAT5) signaling plays a pathogenic role in both hematologic malignancies and solid tumors. In acute myeloid leukemia (AML), internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD) constitutively activate the FLT3 receptor, producing aberrant STAT5 signaling, driving cell survival and proliferation. Understanding STAT5 regulation may aid development of new treatment strategies in STAT5-activated cancers including FLT3-ITD AML. Poly ADP-ribose polymerase (PARP1), upregulated in FLT3-ITD AML, is primarily known as a DNA repair factor, but also regulates a diverse range of proteins through PARylation. Analysis of STAT5 protein sequence revealed putative PARylation sites and we demonstrate a novel PARP1 interaction and direct PARylation of STAT5 in FLT3-ITD AML. Moreover, PARP1 depletion and PARylation inhibition decreased STAT5 protein expression and activity via increased degradation, suggesting that PARP1 PARylation of STAT5 at least in part potentiates aberrant signaling by stabilizing STAT5 protein in FLT3-ITD AML. Importantly for translational significance, PARPis are cytotoxic in numerous STAT5-activated cancer cells and are synergistic with tyrosine kinase inhibitors (TKI) in both TKI-sensitive and TKI-resistant FLT3-ITD AML. Therefore, PARPi may have therapeutic benefit in STAT5-activated and therapy-resistant leukemias and solid tumors.
format article
author Anna J. Dellomo
Rachel Abbotts
Christian L. Eberly
Mariusz Karbowski
Maria R. Baer
Tami J. Kingsbury
Feyruz V. Rassool
author_facet Anna J. Dellomo
Rachel Abbotts
Christian L. Eberly
Mariusz Karbowski
Maria R. Baer
Tami J. Kingsbury
Feyruz V. Rassool
author_sort Anna J. Dellomo
title PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
title_short PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
title_full PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
title_fullStr PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
title_full_unstemmed PARP1 PARylates and stabilizes STAT5 in FLT3-ITD acute myeloid leukemia and other STAT5-activated cancers
title_sort parp1 parylates and stabilizes stat5 in flt3-itd acute myeloid leukemia and other stat5-activated cancers
publisher Elsevier
publishDate 2022
url https://doaj.org/article/1a37956d049b40a797eb0d03b6d03d1b
work_keys_str_mv AT annajdellomo parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT rachelabbotts parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT christianleberly parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT mariuszkarbowski parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT mariarbaer parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT tamijkingsbury parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
AT feyruzvrassool parp1parylatesandstabilizesstat5inflt3itdacutemyeloidleukemiaandotherstat5activatedcancers
_version_ 1718418208383303680