Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia
The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemi...
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| Veröffentlicht in: | Cancers 2020-11, Vol.12 (11), p.3134 |
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| creator | Weinhäuser, Isabel Pereira-Martins, Diego A. Ortiz, Cesar Silveira, Douglas R. Simões, Luíse A. A. Bianco, Thiago M. Araujo, Cleide L. Koury, Luisa C. Melo, Raul A. M. Bittencourt, Rosane I. Pagnano, Katia Pasquini, Ricardo Nunes, Elenaide C. Fagundes, Evandro M. Gloria, Ana B. Kerbauy, Fábio Chauffaille, Maria de Lourdes Keating, Armand Tallman, Martin S. Ribeiro, Raul C. Dillon, Richard Ganser, Arnold Löwenberg, Bob Valk, Peter Lo-Coco, Francesco Sanz, Miguel A. Berliner, Nancy Ammatuna, Emanuele Lucena-Araujo, Antonio R. Schuringa, Jan Jacob Rego, Eduardo M. |
| description | The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated. |
| doi_str_mv | 10.3390/cancers12113134 |
| format | Article |
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A. ; Bianco, Thiago M. ; Araujo, Cleide L. ; Koury, Luisa C. ; Melo, Raul A. M. ; Bittencourt, Rosane I. ; Pagnano, Katia ; Pasquini, Ricardo ; Nunes, Elenaide C. ; Fagundes, Evandro M. ; Gloria, Ana B. ; Kerbauy, Fábio ; Chauffaille, Maria de Lourdes ; Keating, Armand ; Tallman, Martin S. ; Ribeiro, Raul C. ; Dillon, Richard ; Ganser, Arnold ; Löwenberg, Bob ; Valk, Peter ; Lo-Coco, Francesco ; Sanz, Miguel A. ; Berliner, Nancy ; Ammatuna, Emanuele ; Lucena-Araujo, Antonio R. ; Schuringa, Jan Jacob ; Rego, Eduardo M.</creator><creatorcontrib>Weinhäuser, Isabel ; Pereira-Martins, Diego A. ; Ortiz, Cesar ; Silveira, Douglas R. ; Simões, Luíse A. A. ; Bianco, Thiago M. ; Araujo, Cleide L. ; Koury, Luisa C. ; Melo, Raul A. M. ; Bittencourt, Rosane I. ; Pagnano, Katia ; Pasquini, Ricardo ; Nunes, Elenaide C. ; Fagundes, Evandro M. ; Gloria, Ana B. ; Kerbauy, Fábio ; Chauffaille, Maria de Lourdes ; Keating, Armand ; Tallman, Martin S. ; Ribeiro, Raul C. ; Dillon, Richard ; Ganser, Arnold ; Löwenberg, Bob ; Valk, Peter ; Lo-Coco, Francesco ; Sanz, Miguel A. ; Berliner, Nancy ; Ammatuna, Emanuele ; Lucena-Araujo, Antonio R. ; Schuringa, Jan Jacob ; Rego, Eduardo M.</creatorcontrib><description>The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12113134</identifier><identifier>PMID: 33120864</identifier><language>eng</language><publisher>MDPI AG</publisher><subject>Cell proliferation ; Health aspects</subject><ispartof>Cancers, 2020-11, Vol.12 (11), p.3134</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-45c8fa4bf5f5ac1439da40be5b8dc8620a584c6ca45f9b294b466bd32a55f5263</citedby><cites>FETCH-LOGICAL-c398t-45c8fa4bf5f5ac1439da40be5b8dc8620a584c6ca45f9b294b466bd32a55f5263</cites><orcidid>0000-0003-1694-8958 ; 0000-0001-5326-0162 ; 0000-0002-1444-2542 ; 0000-0002-6238-2783 ; 0000-0001-7975-0805 ; 0000-0003-3420-803X ; 0000-0003-1489-1177 ; 0000-0002-9956-5647 ; 0000-0002-3302-4311 ; 0000-0001-5298-9592</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693375/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693375/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Weinhäuser, Isabel</creatorcontrib><creatorcontrib>Pereira-Martins, Diego A.</creatorcontrib><creatorcontrib>Ortiz, Cesar</creatorcontrib><creatorcontrib>Silveira, Douglas R.</creatorcontrib><creatorcontrib>Simões, Luíse A. 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M.</creatorcontrib><creatorcontrib>Bittencourt, Rosane I.</creatorcontrib><creatorcontrib>Pagnano, Katia</creatorcontrib><creatorcontrib>Pasquini, Ricardo</creatorcontrib><creatorcontrib>Nunes, Elenaide C.</creatorcontrib><creatorcontrib>Fagundes, Evandro M.</creatorcontrib><creatorcontrib>Gloria, Ana B.</creatorcontrib><creatorcontrib>Kerbauy, Fábio</creatorcontrib><creatorcontrib>Chauffaille, Maria de Lourdes</creatorcontrib><creatorcontrib>Keating, Armand</creatorcontrib><creatorcontrib>Tallman, Martin S.</creatorcontrib><creatorcontrib>Ribeiro, Raul C.</creatorcontrib><creatorcontrib>Dillon, Richard</creatorcontrib><creatorcontrib>Ganser, Arnold</creatorcontrib><creatorcontrib>Löwenberg, Bob</creatorcontrib><creatorcontrib>Valk, Peter</creatorcontrib><creatorcontrib>Lo-Coco, Francesco</creatorcontrib><creatorcontrib>Sanz, Miguel A.</creatorcontrib><creatorcontrib>Berliner, Nancy</creatorcontrib><creatorcontrib>Ammatuna, Emanuele</creatorcontrib><creatorcontrib>Lucena-Araujo, Antonio R.</creatorcontrib><creatorcontrib>Schuringa, Jan Jacob</creatorcontrib><creatorcontrib>Rego, Eduardo M.</creatorcontrib><title>Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia</title><title>Cancers</title><description>The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. 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Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. 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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Cell proliferation Health aspects |
| title | Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia |
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