Cargando…

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warr...

Descripción completa

Detalles Bibliográficos
Autores principales: Karsa, Mawar, Ronca, Emma, Bongers, Angelika, Mariana, Anna, Moles, Ernest, Failes, Timothy W., Arndt, Greg M., Cheung, Laurence C., Kotecha, Rishi S., Kavallaris, Maria, Haber, Michelle, Norris, Murray D., Henderson, Michelle J., Xiao, Lin, Somers, Klaartje
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811472/
https://www.ncbi.nlm.nih.gov/pubmed/35127484
http://dx.doi.org/10.3389/fonc.2021.779859
_version_ 1784644444035743744
author Karsa, Mawar
Ronca, Emma
Bongers, Angelika
Mariana, Anna
Moles, Ernest
Failes, Timothy W.
Arndt, Greg M.
Cheung, Laurence C.
Kotecha, Rishi S.
Kavallaris, Maria
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
Xiao, Lin
Somers, Klaartje
author_facet Karsa, Mawar
Ronca, Emma
Bongers, Angelika
Mariana, Anna
Moles, Ernest
Failes, Timothy W.
Arndt, Greg M.
Cheung, Laurence C.
Kotecha, Rishi S.
Kavallaris, Maria
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
Xiao, Lin
Somers, Klaartje
author_sort Karsa, Mawar
collection PubMed
description Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.
format Online
Article
Text
id pubmed-8811472
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-88114722022-02-04 Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia Karsa, Mawar Ronca, Emma Bongers, Angelika Mariana, Anna Moles, Ernest Failes, Timothy W. Arndt, Greg M. Cheung, Laurence C. Kotecha, Rishi S. Kavallaris, Maria Haber, Michelle Norris, Murray D. Henderson, Michelle J. Xiao, Lin Somers, Klaartje Front Oncol Oncology Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation. Frontiers Media S.A. 2022-01-20 /pmc/articles/PMC8811472/ /pubmed/35127484 http://dx.doi.org/10.3389/fonc.2021.779859 Text en Copyright © 2022 Karsa, Ronca, Bongers, Mariana, Moles, Failes, Arndt, Cheung, Kotecha, Kavallaris, Haber, Norris, Henderson, Xiao and Somers https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Karsa, Mawar
Ronca, Emma
Bongers, Angelika
Mariana, Anna
Moles, Ernest
Failes, Timothy W.
Arndt, Greg M.
Cheung, Laurence C.
Kotecha, Rishi S.
Kavallaris, Maria
Haber, Michelle
Norris, Murray D.
Henderson, Michelle J.
Xiao, Lin
Somers, Klaartje
Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title_full Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title_fullStr Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title_full_unstemmed Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title_short Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
title_sort systematic in vitro evaluation of a library of approved and pharmacologically active compounds for the identification of novel candidate drugs for kmt2a-rearranged leukemia
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811472/
https://www.ncbi.nlm.nih.gov/pubmed/35127484
http://dx.doi.org/10.3389/fonc.2021.779859
work_keys_str_mv AT karsamawar systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT roncaemma systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT bongersangelika systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT marianaanna systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT molesernest systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT failestimothyw systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT arndtgregm systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT cheunglaurencec systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT kotecharishis systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT kavallarismaria systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT habermichelle systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT norrismurrayd systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT hendersonmichellej systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT xiaolin systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia
AT somersklaartje systematicinvitroevaluationofalibraryofapprovedandpharmacologicallyactivecompoundsfortheidentificationofnovelcandidatedrugsforkmt2arearrangedleukemia