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CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance
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| Veröffentlicht in: | Frontiers in immunology 9(2018) Artikel-Nummer 1676, 15 Seiten |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , |
| Titel: | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance/ Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose |
| Format: | E-Book-Kapitel |
| Sprache: | Englisch |
| veröffentlicht: |
20 July 2018
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| Gesamtaufnahme: |
: Frontiers in immunology, 9(2018) Artikel-Nummer 1676, 15 Seiten
, volume:9 |
| Schlagwörter: | |
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
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| 245 | 1 | 0 | |a CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance |c Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose |
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| 520 | |a Monoclonal anti-CD38-antibodies yield remissions in about one third of relapsed myeloma patients. Depth of response is reported as associated with CD38-expression-height - without a threshold. As basis for clinical trial strategies, we first determined variation of CD38 target-expression including relation to molecular and clinical “high-risk” definitions in AL-amyloidosis, monoclonal gammopathy of unknown significance (MGUS), asymptomatic, symptomatic, and relapsed multiple myeloma. Secondly, we addressed alternative splicing or lack of CD38-expression as potential mechanisms of up-front resistance. We assessed CD138-purified plasma cell samples from 196 AL-amyloidosis, 62 MGUS, 259 asymptomatic, 764 symptomatic, and 90 relapsed myeloma patients, longitudinal pairs of asymptomatic/symptomatic (n = 34) and symptomatic/relapsed myeloma (n = 57) for CD38-expression by gene expression profiling (GEP; n = 1371), RNA-sequencing (n = 593), and flow cytometry (n = 800). CD38-expression was related to chromosomal aberrations, GEP-based assessment of proliferation and risk, and clinical factors. CD38 was expressed in all malignant plasma cell samples at height varying by two orders of magnitude. Expression was significantly lower compared to normal plasma cells with small but significant downregulation in longitudinal sample pairs (GEP, AMM/MM and MM/MMR, respectively). Higher CD38-expression was associated with slower progression to symptomatic and relapsed myeloma and better overall survival in the latter two, but adverse survival in AL-amyloidosis. Molecularly, it was associated with presence of t(4;14) and high-risk according to the UAMS GEP70 risk score. Lower expression was associated with hyperdiploidy but not high-risk aberrations (del17p, gain1q21), GEP-scores or proliferation. Of the two protein coding CD38-transcripts CD38-001 (8-exon, full length) and CD38-005 (truncated), CD38-001 conveyed >97% of reads spanning the respective CD38 splice junction, excluding alternative splicing of receptor binding-sites as mechanism of upfront anti-CD38-treatment resistance. As CD38 was expressed in all plasma cell diseases, upfront resistance against anti-CD38-treatment is thus neither mediated by (complete) absence of CD38-expression nor alternative splicing removing the antibody target sequence, but likely a gradual difference in expression levels. | ||
| 650 | 4 | |a Alternative Splicing | |
| 650 | 4 | |a Amyloidosis | |
| 650 | 4 | |a CD38 | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Multiple Myeloma | |
| 650 | 4 | |a Survival | |
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| 900 | |a Hillengass, J. | ||
| 900 | |a Hegenbart, U. | ||
| 900 | |a Ho, Antony | ||
| 900 | |a Ho, Anthony | ||
| 900 | |a Ho, Anthony D. | ||
| 900 | |a Ho, A. D. | ||
| 900 | |a Ho, A. | ||
| 900 | |a Ho, AD | ||
| 900 | |a Ho, Antony D | ||
| 900 | |a Raab, Marc | ||
| 900 | |a Raab, Marc S. | ||
| 900 | |a Raab, M. S. | ||
| 900 | |a Raab, Marc Steffen | ||
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| contents | Monoclonal anti-CD38-antibodies yield remissions in about one third of relapsed myeloma patients. Depth of response is reported as associated with CD38-expression-height - without a threshold. As basis for clinical trial strategies, we first determined variation of CD38 target-expression including relation to molecular and clinical “high-risk” definitions in AL-amyloidosis, monoclonal gammopathy of unknown significance (MGUS), asymptomatic, symptomatic, and relapsed multiple myeloma. Secondly, we addressed alternative splicing or lack of CD38-expression as potential mechanisms of up-front resistance. We assessed CD138-purified plasma cell samples from 196 AL-amyloidosis, 62 MGUS, 259 asymptomatic, 764 symptomatic, and 90 relapsed myeloma patients, longitudinal pairs of asymptomatic/symptomatic (n = 34) and symptomatic/relapsed myeloma (n = 57) for CD38-expression by gene expression profiling (GEP; n = 1371), RNA-sequencing (n = 593), and flow cytometry (n = 800). CD38-expression was related to chromosomal aberrations, GEP-based assessment of proliferation and risk, and clinical factors. CD38 was expressed in all malignant plasma cell samples at height varying by two orders of magnitude. Expression was significantly lower compared to normal plasma cells with small but significant downregulation in longitudinal sample pairs (GEP, AMM/MM and MM/MMR, respectively). Higher CD38-expression was associated with slower progression to symptomatic and relapsed myeloma and better overall survival in the latter two, but adverse survival in AL-amyloidosis. Molecularly, it was associated with presence of t(4;14) and high-risk according to the UAMS GEP70 risk score. Lower expression was associated with hyperdiploidy but not high-risk aberrations (del17p, gain1q21), GEP-scores or proliferation. Of the two protein coding CD38-transcripts CD38-001 (8-exon, full length) and CD38-005 (truncated), CD38-001 conveyed >97% of reads spanning the respective CD38 splice junction, excluding alternative splicing of receptor binding-sites as mechanism of upfront anti-CD38-treatment resistance. As CD38 was expressed in all plasma cell diseases, upfront resistance against anti-CD38-treatment is thus neither mediated by (complete) absence of CD38-expression nor alternative splicing removing the antibody target sequence, but likely a gradual difference in expression levels. |
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| spelling | Seckinger, Anja 1980- VerfasserIn (DE-588)134177371 (DE-627)562118225 (DE-576)278603734 aut, CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose, 20 July 2018, Text txt rdacontent, Computermedien c rdamedia, Online-Ressource cr rdacarrier, Gesehen am 08.08.2018, Monoclonal anti-CD38-antibodies yield remissions in about one third of relapsed myeloma patients. Depth of response is reported as associated with CD38-expression-height - without a threshold. As basis for clinical trial strategies, we first determined variation of CD38 target-expression including relation to molecular and clinical “high-risk” definitions in AL-amyloidosis, monoclonal gammopathy of unknown significance (MGUS), asymptomatic, symptomatic, and relapsed multiple myeloma. Secondly, we addressed alternative splicing or lack of CD38-expression as potential mechanisms of up-front resistance. We assessed CD138-purified plasma cell samples from 196 AL-amyloidosis, 62 MGUS, 259 asymptomatic, 764 symptomatic, and 90 relapsed myeloma patients, longitudinal pairs of asymptomatic/symptomatic (n = 34) and symptomatic/relapsed myeloma (n = 57) for CD38-expression by gene expression profiling (GEP; n = 1371), RNA-sequencing (n = 593), and flow cytometry (n = 800). CD38-expression was related to chromosomal aberrations, GEP-based assessment of proliferation and risk, and clinical factors. CD38 was expressed in all malignant plasma cell samples at height varying by two orders of magnitude. Expression was significantly lower compared to normal plasma cells with small but significant downregulation in longitudinal sample pairs (GEP, AMM/MM and MM/MMR, respectively). Higher CD38-expression was associated with slower progression to symptomatic and relapsed myeloma and better overall survival in the latter two, but adverse survival in AL-amyloidosis. Molecularly, it was associated with presence of t(4;14) and high-risk according to the UAMS GEP70 risk score. Lower expression was associated with hyperdiploidy but not high-risk aberrations (del17p, gain1q21), GEP-scores or proliferation. Of the two protein coding CD38-transcripts CD38-001 (8-exon, full length) and CD38-005 (truncated), CD38-001 conveyed >97% of reads spanning the respective CD38 splice junction, excluding alternative splicing of receptor binding-sites as mechanism of upfront anti-CD38-treatment resistance. As CD38 was expressed in all plasma cell diseases, upfront resistance against anti-CD38-treatment is thus neither mediated by (complete) absence of CD38-expression nor alternative splicing removing the antibody target sequence, but likely a gradual difference in expression levels., Alternative Splicing, Amyloidosis, CD38, Immunotherapy, Multiple Myeloma, Survival, Hillengaß, Jens 1974- VerfasserIn (DE-588)124918549 (DE-627)368073823 (DE-576)294568298 aut, Emde, Martina VerfasserIn (DE-588)116096193X (DE-627)1024350673 (DE-576)506290433 aut, Beck, Susanne VerfasserIn (DE-588)1164102362 (DE-627)1028488866 (DE-576)508378915 aut, Kimmich, Christoph VerfasserIn (DE-588)1075478413 (DE-627)833305042 (DE-576)443499632 aut, Dittrich, Tobias 1986- VerfasserIn (DE-588)1075743141 (DE-627)833664085 (DE-576)444611495 aut, Hundemer, Michael 1972- VerfasserIn (DE-588)128390549 (DE-627)372634001 (DE-576)297117998 aut, Jauch, Anna VerfasserIn (DE-588)1025525140 (DE-627)722525362 (DE-576)168357496 aut, Hegenbart, Ute VerfasserIn (DE-588)1028373708 (DE-627)73062157X (DE-576)35901903X aut, Raab, Marc-Steffen 1973- VerfasserIn (DE-588)124052460 (DE-627)706520998 (DE-576)293998027 aut, Ho, Anthony Dick 1948- VerfasserIn (DE-588)108692477 (DE-627)504904205 (DE-576)19010466X aut, Schönland, Stefan 1969- VerfasserIn (DE-588)122405226 (DE-627)705896137 (DE-576)293255792 aut, Hose, Dirk 1969- VerfasserIn (DE-588)139824995 (DE-627)613790308 (DE-576)313431698 aut, Enthalten in Frontiers in immunology Lausanne : Frontiers Media, 2010 9(2018) Artikel-Nummer 1676, 15 Seiten Online-Ressource (DE-627)657998354 (DE-600)2606827-8 (DE-576)343624834 1664-3224 nnns, volume:9 year:2018, http://dx.doi.org/10.3389/fimmu.2018.01676 Verlag Resolving-System kostenfrei Volltext, https://www.frontiersin.org/articles/10.3389/fimmu.2018.01676/full Verlag kostenfrei Volltext, http://dx.doi.org/10.3389/fimmu.2018.01676 LFER, LFER 2018-08-13T00:00:00Z |
| spellingShingle | Seckinger, Anja, Hillengaß, Jens, Emde, Martina, Beck, Susanne, Kimmich, Christoph, Dittrich, Tobias, Hundemer, Michael, Jauch, Anna, Hegenbart, Ute, Raab, Marc-Steffen, Ho, Anthony Dick, Schönland, Stefan, Hose, Dirk, CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance, Monoclonal anti-CD38-antibodies yield remissions in about one third of relapsed myeloma patients. Depth of response is reported as associated with CD38-expression-height - without a threshold. As basis for clinical trial strategies, we first determined variation of CD38 target-expression including relation to molecular and clinical “high-risk” definitions in AL-amyloidosis, monoclonal gammopathy of unknown significance (MGUS), asymptomatic, symptomatic, and relapsed multiple myeloma. Secondly, we addressed alternative splicing or lack of CD38-expression as potential mechanisms of up-front resistance. We assessed CD138-purified plasma cell samples from 196 AL-amyloidosis, 62 MGUS, 259 asymptomatic, 764 symptomatic, and 90 relapsed myeloma patients, longitudinal pairs of asymptomatic/symptomatic (n = 34) and symptomatic/relapsed myeloma (n = 57) for CD38-expression by gene expression profiling (GEP; n = 1371), RNA-sequencing (n = 593), and flow cytometry (n = 800). CD38-expression was related to chromosomal aberrations, GEP-based assessment of proliferation and risk, and clinical factors. CD38 was expressed in all malignant plasma cell samples at height varying by two orders of magnitude. Expression was significantly lower compared to normal plasma cells with small but significant downregulation in longitudinal sample pairs (GEP, AMM/MM and MM/MMR, respectively). Higher CD38-expression was associated with slower progression to symptomatic and relapsed myeloma and better overall survival in the latter two, but adverse survival in AL-amyloidosis. Molecularly, it was associated with presence of t(4;14) and high-risk according to the UAMS GEP70 risk score. Lower expression was associated with hyperdiploidy but not high-risk aberrations (del17p, gain1q21), GEP-scores or proliferation. Of the two protein coding CD38-transcripts CD38-001 (8-exon, full length) and CD38-005 (truncated), CD38-001 conveyed >97% of reads spanning the respective CD38 splice junction, excluding alternative splicing of receptor binding-sites as mechanism of upfront anti-CD38-treatment resistance. As CD38 was expressed in all plasma cell diseases, upfront resistance against anti-CD38-treatment is thus neither mediated by (complete) absence of CD38-expression nor alternative splicing removing the antibody target sequence, but likely a gradual difference in expression levels., Alternative Splicing, Amyloidosis, CD38, Immunotherapy, Multiple Myeloma, Survival |
| swb_id_str | 508395097 |
| title | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance |
| title_auth | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance |
| title_full | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose |
| title_fullStr | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose |
| title_full_unstemmed | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose |
| title_in_hierarchy | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance / Anja Seckinger, Jens Hillengass, Martina Emde, Susanne Beck, Christoph Kimmich, Tobias Dittrich, Michael Hundemer, Anna Jauch, Ute Hegenbart, Marc-Steffen Raab, Anthony D. Ho, Stefan Schönland and Dirk Hose, |
| title_short | CD38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma - association with molecular entities, risk, survival, and mechanisms of upfront resistance |
| title_sort | cd38 as immunotherapeutic target in light chain amyloidosis and multiple myeloma association with molecular entities risk survival and mechanisms of upfront resistance |
| topic | Alternative Splicing, Amyloidosis, CD38, Immunotherapy, Multiple Myeloma, Survival |
| topic_facet | Alternative Splicing, Amyloidosis, CD38, Immunotherapy, Multiple Myeloma, Survival |
| url | http://dx.doi.org/10.3389/fimmu.2018.01676, https://www.frontiersin.org/articles/10.3389/fimmu.2018.01676/full |