MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia
Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in...
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creator | Mazzera, Laura Abeltino, Manuela Lombardi, Guerino Cantoni, Anna Maria Jottini, Stefano Corradi, Attilio Ricca, Micaela Rossetti, Elena Armando, Federico Peli, Angelo Ferrari, Anna Martinelli, Giovanni Scupoli, Maria Teresa Visco, Carlo Bonifacio, Massimiliano Ripamonti, Alessia Gambacorti-Passerini, Carlo Bonati, Antonio Perris, Roberto Lunghi, Paolo |
description | Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCR
Y360/Y177
, BCR::ABL1
Y360/Y177
and cytoplasmic ABL1
Y412/T735
dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia. |
doi_str_mv | 10.1038/s41375-023-01940-x |
format | Article |
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Y360/Y177
, BCR::ABL1
Y360/Y177
and cytoplasmic ABL1
Y412/T735
dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-023-01940-x</identifier><identifier>PMID: 37386079</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 13/2 ; 13/31 ; 13/51 ; 13/95 ; 14/63 ; 631/67/1059/2326 ; 631/67/1059/602 ; 631/67/1990/283/1896 ; 64/60 ; 82/29 ; 82/80 ; 96/95 ; Allosteric properties ; Anti-oncogenes ; Arsenic ; Arsenic trioxide ; BCR-ABL protein ; Cancer Research ; Chronic myeloid leukemia ; Critical Care Medicine ; Dephosphorylation ; Drug resistance ; Hematology ; Inhibitors ; Intensive ; Internal Medicine ; Kinases ; Leukemia ; Medicine ; Medicine & Public Health ; Myc protein ; Myeloid leukemia ; Oncology ; Phosphorylation ; Protein-tyrosine kinase ; Tumors ; Tyrosine</subject><ispartof>Leukemia, 2023-08, Vol.37 (8), p.1671-1685</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390x-abb9b400e9386dbeac0a818d95122fc2f240cbf543c421666bef56625a0d9d5b3</citedby><cites>FETCH-LOGICAL-c390x-abb9b400e9386dbeac0a818d95122fc2f240cbf543c421666bef56625a0d9d5b3</cites><orcidid>0000-0003-3488-2948 ; 0000-0001-6058-515X ; 0000-0002-2578-4409 ; 0000-0002-7022-9906 ; 0000-0002-4416-7975 ; 0000-0002-4511-9748 ; 0000-0002-1025-4210 ; 0000-0003-0716-1686</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37386079$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mazzera, Laura</creatorcontrib><creatorcontrib>Abeltino, Manuela</creatorcontrib><creatorcontrib>Lombardi, Guerino</creatorcontrib><creatorcontrib>Cantoni, Anna Maria</creatorcontrib><creatorcontrib>Jottini, Stefano</creatorcontrib><creatorcontrib>Corradi, Attilio</creatorcontrib><creatorcontrib>Ricca, Micaela</creatorcontrib><creatorcontrib>Rossetti, Elena</creatorcontrib><creatorcontrib>Armando, Federico</creatorcontrib><creatorcontrib>Peli, Angelo</creatorcontrib><creatorcontrib>Ferrari, Anna</creatorcontrib><creatorcontrib>Martinelli, Giovanni</creatorcontrib><creatorcontrib>Scupoli, Maria Teresa</creatorcontrib><creatorcontrib>Visco, Carlo</creatorcontrib><creatorcontrib>Bonifacio, Massimiliano</creatorcontrib><creatorcontrib>Ripamonti, Alessia</creatorcontrib><creatorcontrib>Gambacorti-Passerini, Carlo</creatorcontrib><creatorcontrib>Bonati, Antonio</creatorcontrib><creatorcontrib>Perris, Roberto</creatorcontrib><creatorcontrib>Lunghi, Paolo</creatorcontrib><title>MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCR
Y360/Y177
, BCR::ABL1
Y360/Y177
and cytoplasmic ABL1
Y412/T735
dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.</description><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>13/95</subject><subject>14/63</subject><subject>631/67/1059/2326</subject><subject>631/67/1059/602</subject><subject>631/67/1990/283/1896</subject><subject>64/60</subject><subject>82/29</subject><subject>82/80</subject><subject>96/95</subject><subject>Allosteric properties</subject><subject>Anti-oncogenes</subject><subject>Arsenic</subject><subject>Arsenic trioxide</subject><subject>BCR-ABL protein</subject><subject>Cancer Research</subject><subject>Chronic myeloid leukemia</subject><subject>Critical Care Medicine</subject><subject>Dephosphorylation</subject><subject>Drug resistance</subject><subject>Hematology</subject><subject>Inhibitors</subject><subject>Intensive</subject><subject>Internal 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Roberto</au><au>Lunghi, Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2023-08-01</date><risdate>2023</risdate><volume>37</volume><issue>8</issue><spage>1671</spage><epage>1685</epage><pages>1671-1685</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCR
Y360/Y177
, BCR::ABL1
Y360/Y177
and cytoplasmic ABL1
Y412/T735
dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37386079</pmid><doi>10.1038/s41375-023-01940-x</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-3488-2948</orcidid><orcidid>https://orcid.org/0000-0001-6058-515X</orcidid><orcidid>https://orcid.org/0000-0002-2578-4409</orcidid><orcidid>https://orcid.org/0000-0002-7022-9906</orcidid><orcidid>https://orcid.org/0000-0002-4416-7975</orcidid><orcidid>https://orcid.org/0000-0002-4511-9748</orcidid><orcidid>https://orcid.org/0000-0002-1025-4210</orcidid><orcidid>https://orcid.org/0000-0003-0716-1686</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0887-6924 |
ispartof | Leukemia, 2023-08, Vol.37 (8), p.1671-1685 |
issn | 0887-6924 1476-5551 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10400427 |
source | Alma/SFX Local Collection |
subjects | 13/109 13/2 13/31 13/51 13/95 14/63 631/67/1059/2326 631/67/1059/602 631/67/1990/283/1896 64/60 82/29 82/80 96/95 Allosteric properties Anti-oncogenes Arsenic Arsenic trioxide BCR-ABL protein Cancer Research Chronic myeloid leukemia Critical Care Medicine Dephosphorylation Drug resistance Hematology Inhibitors Intensive Internal Medicine Kinases Leukemia Medicine Medicine & Public Health Myc protein Myeloid leukemia Oncology Phosphorylation Protein-tyrosine kinase Tumors Tyrosine |
title | MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T16%3A47%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MEK1/2%20regulate%20normal%20BCR%20and%20ABL1%20tumor-suppressor%20functions%20to%20dictate%20ATO%20response%20in%20TKI-resistant%20Ph+%20leukemia&rft.jtitle=Leukemia&rft.au=Mazzera,%20Laura&rft.date=2023-08-01&rft.volume=37&rft.issue=8&rft.spage=1671&rft.epage=1685&rft.pages=1671-1685&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/s41375-023-01940-x&rft_dat=%3Cproquest_pubme%3E2832580581%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2845350776&rft_id=info:pmid/37386079&rfr_iscdi=true |