DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance
The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria tox...
Uložené v:
| Vydané v: | The Journal of clinical investigation Ročník 129; číslo 11; s. 5005 - 5019 |
|---|---|
| Hlavní autori: | , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
American Society for Clinical Investigation
01.11.2019
|
| Predmet: | |
| ISSN: | 0021-9738, 1558-8238, 1558-8238 |
| On-line prístup: | Získať plný text |
| Tagy: |
Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
|
| Abstract | The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies. |
|---|---|
| AbstractList | The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp’s ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies. The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies. The interleukin-3 receptor [alpha] subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP- ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies. The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drugdependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies. |
| Audience | Academic |
| Author | Lindsay, Ross W. Ghandi, Mahmoud Brooks, Christopher L. Stephansky, Jason Weinstock, David M. Craig, Jeffrey W. Johannessen, Cory M. Christie, Amanda L. Lane, Andrew A. Montero, Joan Pozdnyakova, Olga Aster, Jon C. Jones, Kristen L. Letai, Anthony Pastika, Timothy Togami, Katsuhiro Johnson, Carl A. |
| AuthorAffiliation | 4 Stemline Therapeutics, New York, New York, USA 2 Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA 3 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA |
| AuthorAffiliation_xml | – name: 2 Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA – name: 3 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA – name: 4 Stemline Therapeutics, New York, New York, USA – name: 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA |
| Author_xml | – sequence: 1 givenname: Katsuhiro surname: Togami fullname: Togami, Katsuhiro – sequence: 2 givenname: Timothy surname: Pastika fullname: Pastika, Timothy – sequence: 3 givenname: Jason surname: Stephansky fullname: Stephansky, Jason – sequence: 4 givenname: Mahmoud orcidid: 0000-0003-1897-2265 surname: Ghandi fullname: Ghandi, Mahmoud – sequence: 5 givenname: Amanda L. surname: Christie fullname: Christie, Amanda L. – sequence: 6 givenname: Kristen L. surname: Jones fullname: Jones, Kristen L. – sequence: 7 givenname: Carl A. surname: Johnson fullname: Johnson, Carl A. – sequence: 8 givenname: Ross W. surname: Lindsay fullname: Lindsay, Ross W. – sequence: 9 givenname: Christopher L. surname: Brooks fullname: Brooks, Christopher L. – sequence: 10 givenname: Anthony orcidid: 0000-0002-1993-9013 surname: Letai fullname: Letai, Anthony – sequence: 11 givenname: Jeffrey W. orcidid: 0000-0003-1295-3258 surname: Craig fullname: Craig, Jeffrey W. – sequence: 12 givenname: Olga surname: Pozdnyakova fullname: Pozdnyakova, Olga – sequence: 13 givenname: David M. orcidid: 0000-0002-8724-3907 surname: Weinstock fullname: Weinstock, David M. – sequence: 14 givenname: Joan surname: Montero fullname: Montero, Joan – sequence: 15 givenname: Jon C. surname: Aster fullname: Aster, Jon C. – sequence: 16 givenname: Cory M. surname: Johannessen fullname: Johannessen, Cory M. – sequence: 17 givenname: Andrew A. surname: Lane fullname: Lane, Andrew A. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31437130$$D View this record in MEDLINE/PubMed |
| BookMark | eNqNk01r3DAQhk1JaTZpD_0DxVAo7cGJZMmyfAksm35sCQ306ypkeWwr2NJWktNuf321JNlk2z1UQgxIz7yaYWaOkgNjDSTJc4xOMC7z04-LJc55UeJHyQwXBc94TvhBMkMox1lVEn6YHHl_hRCmtKBPkkOCKSkxQbPk9_mneTpC6NdDcNL4Fpz0kGrT61oHbU1qr8EpO4JPG73qQy9H3UC6kqH_KddpA61WGkw8Pp1MA25Ya9Oli3OckyxI10GAJg0OZBjBhNSB1z5Io-Bp8riVg4dnt_Y4-fbu7dfFh-zi8v1yMb_IFCtJyJqaIoIqTmVZUCwLyVrZUq7qltYNAKYMJCc1ZyguLquSlapqi4K1JSXAGDlOzm50V1M9QqNiFE4OYuX0KN1aWKnF7ovRvejstWAcVzhHUeD1rYCzPybwQYzaKxgGacBOXuQEFbTkjOQRffkXemUnZ2J6kcKEUFTk5T3VyQGENq2N_6qNqJizmGpBK7SJO9tDdWBiiYbYAK2O1zv8yR4-7gZGrfY6vNlxiEyAX6GTk_di-eXz_7OX33fZVw_YHuQQem-HadNOfhd88bAy25LctWcETm8A5az3DlqhdJAbnZiaHgRGYjMAYjsA93FuPe5E_2X_ABRkAoY |
| CitedBy_id | crossref_primary_10_1080_10717544_2021_1934191 crossref_primary_10_1080_14712598_2020_1701651 crossref_primary_10_1002_ajh_27737 crossref_primary_10_1182_blood_2020007897 crossref_primary_10_1182_blood_2020008745 crossref_primary_10_1080_14656566_2022_2029846 crossref_primary_10_1080_10428194_2025_2498046 crossref_primary_10_1080_10428194_2024_2343029 crossref_primary_10_1080_14737140_2020_1776120 crossref_primary_10_1038_s41467_022_29669_8 crossref_primary_10_2147_OTT_S228342 crossref_primary_10_3390_ijms26062732 crossref_primary_10_1016_j_hoc_2020_01_001 crossref_primary_10_1016_j_hoc_2020_01_002 crossref_primary_10_3892_ol_2024_14354 crossref_primary_10_1016_j_hoc_2020_01_004 crossref_primary_10_1016_j_critrevonc_2020_102928 crossref_primary_10_1016_j_hoc_2020_01_005 crossref_primary_10_1016_j_hoc_2020_01_006 crossref_primary_10_3390_ijms24032718 crossref_primary_10_3390_jcm13041082 crossref_primary_10_3389_fonc_2024_1384172 crossref_primary_10_1182_bloodadvances_2023011586 crossref_primary_10_3389_fonc_2021_656218 crossref_primary_10_1007_s12308_021_00479_z crossref_primary_10_1097_MD_0000000000032904 crossref_primary_10_3390_ijms25031454 crossref_primary_10_1016_j_critrevonc_2023_104186 crossref_primary_10_1182_bloodadvances_2019000173 crossref_primary_10_1093_ajcp_aqac174 crossref_primary_10_1080_17474086_2021_1988848 crossref_primary_10_3390_cancers14153767 crossref_primary_10_1016_S2152_2650_20_30466_3 crossref_primary_10_1016_j_clml_2021_02_008 crossref_primary_10_1080_17474086_2023_2174521 crossref_primary_10_1016_j_leukres_2024_107479 crossref_primary_10_1016_j_clml_2021_05_018 crossref_primary_10_1016_j_bneo_2025_100086 crossref_primary_10_1159_000533990 crossref_primary_10_1080_13543784_2023_2179482 crossref_primary_10_3389_fonc_2021_624742 crossref_primary_10_3390_cancers11091358 crossref_primary_10_1016_S2152_2650_22_00658_9 crossref_primary_10_1186_s11658_024_00674_7 crossref_primary_10_3389_fimmu_2021_695865 crossref_primary_10_1016_j_hoc_2020_01_007 crossref_primary_10_1038_s41375_023_01968_z crossref_primary_10_1182_bloodadvances_2023011721 crossref_primary_10_1080_10428194_2024_2305288 crossref_primary_10_3390_cancers13164113 crossref_primary_10_1002_ajh_26417 crossref_primary_10_1038_s41467_021_26683_0 crossref_primary_10_1080_14712598_2023_2174015 crossref_primary_10_1182_bloodadvances_2021006645 crossref_primary_10_1177_1078155220951850 crossref_primary_10_3389_fmed_2024_1425833 crossref_primary_10_1016_j_yamp_2023_07_001 crossref_primary_10_1080_10428194_2021_1927021 crossref_primary_10_1080_17474086_2021_1935855 crossref_primary_10_1186_s12935_021_01928_6 crossref_primary_10_1038_s41375_020_0777_1 crossref_primary_10_1002_hon_3234 crossref_primary_10_1172_JCI132443 crossref_primary_10_1002_jha2_70070 |
| Cites_doi | 10.1532/IJH97.04116 10.1016/j.cell.2017.06.010 10.1016/j.cell.2012.08.038 10.1111/j.1365-2141.2009.07679.x 10.3390/biomedicines7010006 10.3109/10409238.2013.831023 10.1016/j.ccell.2016.03.008 10.1016/j.gde.2004.12.006 10.1038/sj.leu.2402446 10.1186/2050-7771-2-4 10.1038/s41375-018-0210-1 10.1016/j.leukres.2013.08.005 10.1073/pnas.1714512115 10.1186/s13059-014-0550-8 10.1182/asheducation-2016.1.16 10.1038/sj.leu.2401903 10.1073/pnas.1206933109 10.1038/bcj.2014.39 10.1073/pnas.0914878107 10.1056/NEJMoa1815105 10.1016/j.csbj.2016.09.003 10.1016/j.ccell.2016.10.002 10.1073/pnas.1501958112 10.1016/j.cell.2014.09.029 10.1101/gad.1162204 10.1038/s41467-018-04356-9 10.1093/bioinformatics/bts196 10.1016/j.freeradbiomed.2013.10.015 10.1007/s00294-017-0711-x 10.1182/blood-2014-04-566737 10.3390/toxins5061180 10.1016/S0041-0101(01)00165-9 10.1158/2159-8290.CD-16-0999 10.1007/s11899-018-0489-z 10.1182/blood-2014-06-578633 10.1186/gb-2011-12-1-r1 10.1038/s41375-018-0265-z 10.1126/science.1206727 10.1016/j.cell.2015.01.042 10.3390/toxins5050958 10.1073/pnas.1512863112 |
| ContentType | Journal Article |
| Copyright | COPYRIGHT 2019 American Society for Clinical Investigation Copyright American Society for Clinical Investigation Nov 2019 2019 American Society for Clinical Investigation 2019 American Society for Clinical Investigation |
| Copyright_xml | – notice: COPYRIGHT 2019 American Society for Clinical Investigation – notice: Copyright American Society for Clinical Investigation Nov 2019 – notice: 2019 American Society for Clinical Investigation 2019 American Society for Clinical Investigation |
| DBID | AAYXX CITATION CGR CUY CVF ECM EIF NPM IOV ISR 3V. 7RV 7X7 7XB 88A 88E 8AO 8FE 8FH 8FI 8FJ 8FK ABUWG AFKRA AZQEC BBNVY BEC BENPR BHPHI CCPQU DWQXO FYUFA GHDGH GNUQQ HCIFZ K9. KB0 LK8 M0S M1P M7P NAPCQ PHGZM PHGZT PJZUB PKEHL PPXIY PQEST PQGLB PQQKQ PQUKI PRINS S0X 7X8 5PM |
| DOI | 10.1172/JCI128571 |
| DatabaseName | CrossRef Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed Gale In Context: Opposing Viewpoints Gale In Context: Science ProQuest Central (Corporate) Nursing & Allied Health Database Health & Medical Collection ProQuest Central (purchase pre-March 2016) Biology Database (Alumni Edition) Medical Database (Alumni Edition) ProQuest Pharma Collection ProQuest SciTech Collection ProQuest Natural Science Collection Hospital Premium Collection Hospital Premium Collection (Alumni Edition) ProQuest Central (Alumni) (purchase pre-March 2016) ProQuest Central ProQuest Central UK/Ireland ProQuest Central Essentials Biological Science Collection eLibrary ProQuest Central Natural Science Collection ProQuest One Community College ProQuest Central Korea Health Research Premium Collection Health Research Premium Collection (Alumni) ProQuest Central Student SciTech Premium Collection ProQuest Health & Medical Complete (Alumni) Nursing & Allied Health Database (Alumni Edition) ProQuest Biological Science Collection Health & Medical Collection (Alumni Edition) Medical Database Biological Science Database Nursing & Allied Health Premium ProQuest Central Premium ProQuest One Academic (New) ProQuest Health & Medical Research Collection ProQuest One Academic Middle East (New) ProQuest One Health & Nursing ProQuest One Academic Eastern Edition (DO NOT USE) ProQuest One Applied & Life Sciences ProQuest One Academic (retired) ProQuest One Academic UKI Edition ProQuest Central China SIRS Editorial MEDLINE - Academic PubMed Central (Full Participant titles) |
| DatabaseTitle | CrossRef MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) ProQuest Central Student ProQuest One Academic Middle East (New) ProQuest Central Essentials SIRS Editorial elibrary ProQuest Health & Medical Complete (Alumni) ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College ProQuest One Health & Nursing ProQuest Natural Science Collection ProQuest Pharma Collection ProQuest Central China ProQuest Biology Journals (Alumni Edition) ProQuest Central ProQuest One Applied & Life Sciences ProQuest Health & Medical Research Collection Health Research Premium Collection Health and Medicine Complete (Alumni Edition) Natural Science Collection ProQuest Central Korea Health & Medical Research Collection Biological Science Collection ProQuest Central (New) ProQuest Medical Library (Alumni) ProQuest Biological Science Collection ProQuest One Academic Eastern Edition ProQuest Nursing & Allied Health Source ProQuest Hospital Collection Health Research Premium Collection (Alumni) Biological Science Database ProQuest SciTech Collection ProQuest Hospital Collection (Alumni) Nursing & Allied Health Premium ProQuest Health & Medical Complete ProQuest Medical Library ProQuest One Academic UKI Edition ProQuest Nursing & Allied Health Source (Alumni) ProQuest One Academic ProQuest One Academic (New) ProQuest Central (Alumni) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE MEDLINE - Academic ProQuest Central Student |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7RV name: Nursing & Allied Health Database url: https://search.proquest.com/nahs sourceTypes: Aggregation Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1558-8238 |
| EndPage | 5019 |
| ExternalDocumentID | PMC6819120 A609854906 31437130 10_1172_JCI128571 |
| Genre | Research Support, Non-U.S. Gov't Journal Article Research Support, N.I.H., Extramural |
| GeographicLocations | United States Massachusetts United States--US |
| GeographicLocations_xml | – name: Massachusetts – name: United States – name: United States--US |
| GrantInformation_xml | – fundername: NCI NIH HHS grantid: R37 CA225191 – fundername: NCI NIH HHS grantid: P01 CA066996 – fundername: ; grantid: CA066996 – fundername: ; grantid: D2015<2010>037 – fundername: Ludwig Cancer Research grantid: NA – fundername: ; grantid: 2017065 – fundername: ; grantid: NA – fundername: ; grantid: CA225191-01 – fundername: Stemline Therapeutics grantid: NA – fundername: ; grantid: RYC-2015-18357 |
| GroupedDBID | --- -~X .55 .XZ 08G 08P 29K 354 36B 5GY 5RE 5RS 7RV 7X7 88E 8AO 8F7 8FE 8FH 8FI 8FJ 8R4 8R5 AAWTL AAYXX ABOCM ABPMR ABUWG ACGFO ACIHN ACNCT ACPRK ADBBV ADPDF AEAQA AENEX AFCHL AFFHD AFKRA AHMBA ALMA_UNASSIGNED_HOLDINGS AOIJS ASPBG AVWKF AZFZN BAWUL BBNVY BCU BEC BENPR BHPHI BKEYQ BLC BPHCQ BVXVI CCPQU CITATION CS3 D-I DIK DU5 E3Z EBD EBS EJD EMB EMOBN EX3 F5P FRP FYUFA GROUPED_DOAJ GX1 HCIFZ HMCUK HYE IAO IEA IHR IHW INH IOF IOV IPO ISR ITC KQ8 L7B LK8 M1P M5~ M7P NAPCQ OBH OCB ODZKP OFXIZ OGEVE OHH OK1 OVD OVIDX OVT P2P P6G PHGZM PHGZT PJZUB PPXIY PQGLB PQQKQ PROAC PSQYO Q2X RPM S0X SJFOW SV3 TEORI TR2 TVE UKHRP VVN W2D WH7 WOQ WOW X7M XSB YFH YHG YKV YOC ZY1 ~H1 ALIPV CGR CUY CVF ECM EIF NPM 3V. 7XB 88A 8FK AZQEC DWQXO GNUQQ K9. PKEHL PQEST PQUKI PRINS 7X8 PUEGO 5PM |
| ID | FETCH-LOGICAL-c673t-db4030984a7541a5a6faf48cbf4bdee146ea83b8600008a9767c9f556f743e663 |
| IEDL.DBID | M7P |
| ISICitedReferencesCount | 69 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000493974100048&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0021-9738 1558-8238 |
| IngestDate | Tue Nov 04 01:44:12 EST 2025 Fri Sep 05 07:01:00 EDT 2025 Tue Oct 07 05:11:07 EDT 2025 Sat Nov 29 13:12:06 EST 2025 Sat Nov 29 11:50:01 EST 2025 Sat Nov 29 10:02:50 EST 2025 Wed Nov 26 10:11:14 EST 2025 Wed Nov 26 09:31:54 EST 2025 Thu May 22 21:21:59 EDT 2025 Mon Jul 21 05:59:16 EDT 2025 Sat Nov 29 01:34:32 EST 2025 Tue Nov 18 21:04:17 EST 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 11 |
| Keywords | Oncology Hematology Molecular biology Leukemias Toxins/drugs/xenobiotics |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c673t-db4030984a7541a5a6faf48cbf4bdee146ea83b8600008a9767c9f556f743e663 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: KT, TP, and JS are co–first authors. |
| ORCID | 0000-0003-1897-2265 0000-0002-1993-9013 0000-0003-1295-3258 0000-0002-8724-3907 |
| OpenAccessLink | http://www.jci.org/articles/view/128571/files/pdf |
| PMID | 31437130 |
| PQID | 2313340527 |
| PQPubID | 42166 |
| PageCount | 15 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_6819120 proquest_miscellaneous_2305478632 proquest_journals_2313340527 gale_infotracmisc_A609854906 gale_infotracgeneralonefile_A609854906 gale_infotracacademiconefile_A609854906 gale_incontextgauss_ISR_A609854906 gale_incontextgauss_IOV_A609854906 gale_healthsolutions_A609854906 pubmed_primary_31437130 crossref_citationtrail_10_1172_JCI128571 crossref_primary_10_1172_JCI128571 |
| PublicationCentury | 2000 |
| PublicationDate | 2019-11-01 |
| PublicationDateYYYYMMDD | 2019-11-01 |
| PublicationDate_xml | – month: 11 year: 2019 text: 2019-11-01 day: 01 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States – name: Ann Arbor |
| PublicationTitle | The Journal of clinical investigation |
| PublicationTitleAlternate | J Clin Invest |
| PublicationYear | 2019 |
| Publisher | American Society for Clinical Investigation |
| Publisher_xml | – name: American Society for Clinical Investigation |
| References | B20 B21 B22 B23 B24 B25 B26 B27 B28 B29 Ehninger (B3) 2014; 4 Alkharabsheh (B8) 2019; 7 B30 B31 B10 B32 B11 B33 B12 B34 B13 B35 B14 B36 B15 B37 B16 B38 B17 B39 B18 B19 B1 B2 Sullivan (B6) 2016; 2016 B4 B5 B7 B9 B40 B41 31609247 - J Clin Invest. 2019 Nov 1;129(11):4590-4592 |
| References_xml | – ident: B37 doi: 10.1532/IJH97.04116 – ident: B14 doi: 10.1016/j.cell.2017.06.010 – ident: B26 doi: 10.1016/j.cell.2012.08.038 – ident: B5 doi: 10.1111/j.1365-2141.2009.07679.x – volume: 7 issue: 1 year: 2019 ident: B8 article-title: Clinical activity and tolerability of SL-401 (tagraxofusp): recombinant diphtheria toxin and interleukin-3 in hematologic malignancies publication-title: Biomedicines doi: 10.3390/biomedicines7010006 – ident: B18 doi: 10.3109/10409238.2013.831023 – ident: B27 doi: 10.1016/j.ccell.2016.03.008 – ident: B35 doi: 10.1016/j.gde.2004.12.006 – ident: B1 doi: 10.1038/sj.leu.2402446 – ident: B2 doi: 10.1186/2050-7771-2-4 – ident: B29 doi: 10.1038/s41375-018-0210-1 – ident: B21 doi: 10.1016/j.leukres.2013.08.005 – ident: B30 doi: 10.1073/pnas.1714512115 – ident: B41 doi: 10.1186/s13059-014-0550-8 – volume: 2016 start-page: 16 issue: 1 year: 2016 ident: B6 article-title: Treatment of blastic plasmacytoid dendritic cell neoplasm publication-title: Hematology Am Soc Hematol Educ Program doi: 10.1182/asheducation-2016.1.16 – ident: B7 doi: 10.1038/sj.leu.2401903 – ident: B32 doi: 10.1073/pnas.1206933109 – volume: 4 year: 2014 ident: B3 article-title: Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia publication-title: Blood Cancer J doi: 10.1038/bcj.2014.39 – ident: B22 doi: 10.1073/pnas.0914878107 – ident: B10 doi: 10.1056/NEJMoa1815105 – ident: B13 doi: 10.1016/j.csbj.2016.09.003 – ident: B15 doi: 10.1016/j.ccell.2016.10.002 – ident: B28 doi: 10.1073/pnas.1501958112 – ident: B19 doi: 10.1016/j.cell.2014.09.029 – ident: B36 doi: 10.1101/gad.1162204 – ident: B39 doi: 10.1038/s41467-018-04356-9 – ident: B40 doi: 10.1093/bioinformatics/bts196 – ident: B33 doi: 10.1016/j.freeradbiomed.2013.10.015 – ident: B34 doi: 10.1007/s00294-017-0711-x – ident: B11 doi: 10.1182/blood-2014-04-566737 – ident: B17 doi: 10.3390/toxins5061180 – ident: B16 doi: 10.1016/S0041-0101(01)00165-9 – ident: B24 doi: 10.1158/2159-8290.CD-16-0999 – ident: B4 doi: 10.1007/s11899-018-0489-z – ident: B9 doi: 10.1182/blood-2014-06-578633 – ident: B38 doi: 10.1186/gb-2011-12-1-r1 – ident: B12 doi: 10.1038/s41375-018-0265-z – ident: B25 doi: 10.1126/science.1206727 – ident: B23 doi: 10.1016/j.cell.2015.01.042 – ident: B20 doi: 10.3390/toxins5050958 – ident: B31 doi: 10.1073/pnas.1512863112 – reference: 31609247 - J Clin Invest. 2019 Nov 1;129(11):4590-4592 |
| SSID | ssj0014454 |
| Score | 2.5571663 |
| Snippet | The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid... The interleukin-3 receptor [alpha] subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic... |
| SourceID | pubmedcentral proquest gale pubmed crossref |
| SourceType | Open Access Repository Aggregation Database Index Database Enrichment Source |
| StartPage | 5005 |
| SubjectTerms | Acute myelocytic leukemia Acute myeloid leukemia ADP-ribosylation Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Azacitidine - pharmacology Biomarkers Biomedical research Blinatumomab Blood cancer Bone marrow Cancer Cancer therapies CD123 antigen Cell Line, Tumor Chemotherapy CpG islands Cytokines Cytotoxicity Dendritic cells Dendritic Cells - metabolism Dendritic Cells - pathology Deoxyribonucleic acid Diphtheria Diphtheria toxin DNA DNA Methylation DNA methyltransferase Drug Delivery Systems Drug dosages Enzymes Female Genomes Hematologic Neoplasms - drug therapy Hematologic Neoplasms - metabolism Hematologic Neoplasms - pathology Humans Inotuzumab ozogamicin Interleukin 3 Interleukin-3 Receptor alpha Subunit - metabolism Interleukins Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Male Methylation Mice Mice, Nude Minor Histocompatibility Antigens - metabolism Mitochondria Myeloid leukemia Neoplasm Proteins - metabolism Patients Recombinant Fusion Proteins - pharmacology Ribosylation Scientific equipment industry Tagraxofusp Transferases Treatment resistance Tumor Suppressor Proteins - metabolism Tumors Xenograft Model Antitumor Assays Xenografts |
| Title | DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/31437130 https://www.proquest.com/docview/2313340527 https://www.proquest.com/docview/2305478632 https://pubmed.ncbi.nlm.nih.gov/PMC6819120 |
| Volume | 129 |
| WOSCitedRecordID | wos000493974100048&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| journalDatabaseRights | – providerCode: PRVPQU databaseName: Biological Science Database customDbUrl: eissn: 1558-8238 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014454 issn: 0021-9738 databaseCode: M7P dateStart: 20020701 isFulltext: true titleUrlDefault: http://search.proquest.com/biologicalscijournals providerName: ProQuest – providerCode: PRVPQU databaseName: Health & Medical Collection customDbUrl: eissn: 1558-8238 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014454 issn: 0021-9738 databaseCode: 7X7 dateStart: 20020701 isFulltext: true titleUrlDefault: https://search.proquest.com/healthcomplete providerName: ProQuest – providerCode: PRVPQU databaseName: Nursing & Allied Health Database customDbUrl: eissn: 1558-8238 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014454 issn: 0021-9738 databaseCode: 7RV dateStart: 20020701 isFulltext: true titleUrlDefault: https://search.proquest.com/nahs providerName: ProQuest – providerCode: PRVPQU databaseName: ProQuest Central Database Suite (ProQuest) customDbUrl: eissn: 1558-8238 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0014454 issn: 0021-9738 databaseCode: BENPR dateStart: 20020701 isFulltext: true titleUrlDefault: https://www.proquest.com/central providerName: ProQuest |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3fb9MwELbYhhAv_P4RGMUgBLxESxPHTp5Q6TYxJEpVYOpb5NjOGqmkpWlBE_88d44bFjQhJF7y4q-tU9t3n-277wh5YSQ3gdHSV6GIfcajAuxggidiQah5HhRBoGyxCTEaJdNpOnYHbrULq9zaRGuo9ULhGfkB8JAoAnYRijfLbz5WjcLbVVdCY4fsoUpCZEP3xu0tAmOxU2Hu-6mIEqcsBD774P3wBCxzLPodf_SnVb7glrohkxd80PHN_-39LXLDsU86aKbLbXLFVHfItQ_ufv0u-Xk4GlAsKn0-X1tGa1bg5WhZzcrcxnZRjPiEnzQ11eVytp7Jr6U2FOsa_5DnVBsUpDBY8LemmJ62mmMaFR0eguvyaRN2bjRtw9sp7PaRwcLUu0e-HB99Hr7zXXkGX3ERrX2dM7yfSZgUMevLWPJCFixRecFybQyYYCOTKE-45aUSeI9QaRHHvADWYoDp3Ce71aIyDwkNVaAYbK4ipgImDE8Vl2B6dJFqqRJeeOT1dpAy5bTLsYTGPLN7GBFm7Xh65HkLXTaCHZeBnuJIZ02uabvIswGH94Edc8DhaywCJTIqjME5k5u6zk4-nv4D6NOkA3rlQMUC-qyky3uAN0fprQ7yZQd51giPXwbc7wDBIqhu83YSZs4i1dnvGeiRZ20zfhKj7Cqz2CAmQHk3HoUeedDM9_Y_jIBYCyA8HhGdldACUKe821KVM6tXzvFQIAwe_b1bj8l1IKNpk-e5T3bXq415Qq6q7-uyXvXIjpic4nMq7DPpkb23R6PxpGeX_C8MDFus |
| linkProvider | ProQuest |
| linkToHtml | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1Lb9NAEF6VgoAL70eg0AXx6MWqY6937QNCUULV0DagtlS9uevddWMpOCF2qCL-E7-RGb-oUYW49MB5v1heZ3Zmdvebbwh5ZSQ3ttHSUo7wLMbdGPygjyditqN5ZMe2rYpmE2I08o-Pg88r5GddC4O0ytonFo5aTxWekW9CHuK6kF044v3sm4Vdo_B2tW6hUZrFjlmewZYtezccwP_72nG2Phz2t62qq4CluHBzS0cMrxV8JoXHutKTPJYx81UUs0gbA57DSN-NfF6kUxLCtVBB7Hk8hmBrIEDDc6-Qq-DHu0ghE_tHza0FY16l-ty1AuH6lZIR5AibH_tDiASe6Lbi359R4FwYbFM0z8W8rdv_29e6Q25V2TXtlcvhLlkx6T1yfa_iD9wnPwajHsWm2ctJXmTsZg5RnCbpOIkK7hpFRitM0WRUJ7NxPpZfE20o9m0-k0uqDQpuGGxonFEsv5tPsEyM9gcQmi1a0uqNpg19n85Nhhk6LK0H5MulTP0hWU2nqXlMqKNsxWDz6DJlM2F4oLgE16rjQEvl87hDNmqjCFWlzY4tQiZhsUcTTtjYT4e8bKCzUpDkItA6WlZY1tI2TizscZiPxwKbw2MKBEqApMgxOpWLLAuHn47-AXSw3wK9rUDxFN5ZyaquA2aO0mIt5JsW8rQUVr8IuNYCgsdT7eHa6MPK42bhb4vvkBfNMP4SWYSpmS4QY6N8HXedDnlUrq_mG7qwcRCQ0HWIaK28BoA67O2RNBkXeuwcDz0c-8nfX2ud3Ng-3NsNd4ejnafkJiTeQVnTukZW8_nCPCPX1Pc8yebPC6dCycllr8tffdOzoQ |
| linkToPdf | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1Jb9NAFB6Vgiou7Eug0AGxXaw69njGPiAUJUSEQojY1JsZz9JYCk6wE6qIf8av4z3bMTWqEJceOM8Xy-O8dea97xHyyEhuXKOlozwROIz7FuxgiCdirqd54lrXVeWwCTEeh4eH0WSL_Nz0wmBZ5cYmloZazxWeke9DHOL7EF1Aqm7rsojJYPhi8c3BCVJ407oZp1GJyIFZH0P6VjwfDeC_fux5w5cf-6-cesKAo7jwl45OGF4xhEyKgHVlILmVloUqsSzRxoAVMTL0k5CXoZUE1y1UZIOAW3C8Bpw1PPccOS-QtLwsG5w0NxiMBTUDdNeJhB_WrEYQL-y_7o_AKwSi2_KFf3qEEy6xXa55wv8NL__PX-4KuVRH3bRXqclVsmWya2TnbV1XcJ38GIx7FIdpr2fLMpI3OXh3mmbTNClr2ihWusJ2TUF1upgup_Jrqg3Fec7Hck21QSIOg4OOC4ptefkM28dofwAu26FVub3RtCnrp7kpMHIHlbtBPp3J1m-S7WyemduEespVDJJKnymXCcMjxSWYXG0jLVXIbYc82whIrGrOdhwdMovL3E14cSNLHfKwgS4qopLTQHsoZXHVY9sYt7jHYT8Bi1wOjykRSA2SoagcyVVRxKN3n_8B9OF9C_S0Btk5vLOSdb8H7Bwpx1rIJy3kUUW4fhpwtwUES6jayxsFiGtLXMS_pb9DHjTL-EusLszMfIUYF2ntuO91yK1K15pv6ENCISDQ6xDR0sIGgPzs7ZUsnZY87RwPQzz3zt9fa4_sgDrGb0bjg7vkIsTjUdXquku2l_nK3CMX1PdlWuT3S_tCyZezVstfB2-8Qw |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=DNA+methyltransferase+inhibition+overcomes+diphthamide+pathway+deficiencies+underlying+CD123-targeted+treatment+resistance&rft.jtitle=The+Journal+of+clinical+investigation&rft.au=Togami%2C+Katsuhiro&rft.au=Pastika%2C+Timothy&rft.au=Stephansky%2C+Jason&rft.au=Ghandi%2C+Mahmoud&rft.date=2019-11-01&rft.pub=American+Society+for+Clinical+Investigation&rft.issn=0021-9738&rft.volume=129&rft.issue=11&rft_id=info:doi/10.1172%2FJCI128571&rft.externalDBID=ISR&rft.externalDocID=A609854906 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0021-9738&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0021-9738&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0021-9738&client=summon |