Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia

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Weinhauser, Isabel ^{[1, 2, 3, 4]} ; Pereira-Martins, Diego A. ^{[1, 2, 3, 4]} ; Ortiz, Cesar ^{[1, 2, 3]} ; Silveira, Douglas R. ^{[5, 6]} ; Simoes, Luise A. A. ^{[3, 5]} ; Bianco, Thiago M. ^{[1, 2]} ; Araujo, Cleide L. ^[3] ; Koury, Luisa C. ^{[1, 2]} ; Melo, Raul A. M. ^[7] ; Bittencourt, Rosane I. ^[8] ; Pagnano, Katia ^[9] ; Pasquini, Ricardo ^[10] ; Nunes, Elenaide C. ^[10] ; Fagundes, Evandro M. ^[11] ; Gloria, Ana B. ^[11] ; Kerbauy, Fabio ^[12] ; Chauffaille, Maria de Lourdes ^[12] ; Keating, Armand ^[13] ; Tallman, Martin S. ^[14] ; Ribeiro, Raul C. ^[15] ; Dillon, Richard ^[16] ; Ganser, Arnold ^[17] ; Lowenberg, Bob ^[18] ; Valk, Peter ^[18] ; Lo-Coco, Francesco ^{[19, 20]} ; Sanz, Miguel A. ^{[21, 22]} ; Berliner, Nancy ^[23] ; Ammatuna, Emanuele ^[4] ; Lucena-Araujo, Antonio R. ^[24] ; Schuringa, Jan Jacob ^[4] ; Rego, Eduardo M. ^{[3, 5]}

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^[1] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Internal Med, BR-14048900 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Med Images Hematol & Clin Oncol, BR-14048900 Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Ctr Cell Based Therapy, BR-14051060 Ribeirao Preto - Brazil

^[4] Univ Groningen, Univ Med Ctr Groningen, Canc Res Ctr Groningen, Dept Expt Hematol, NL-9700 RB Groningen - Netherlands

^[5] Univ Sao Paulo, Fac Med, LIM31, Hematol Div, BR-05403000 Sao Paulo - Brazil

^[6] AC Camargo Canc Ctr, Dept Hematol, BR-01525001 Sao Paulo - Brazil

^[7] Univ Pernambuco, Dept Internal Med, BR-50100130 Recife, PE - Brazil

^[8] Univ Fed Rio Grande do Sul, Hematol Div, BR-96 20019 Porto Alegre, RS - Brazil

^[9] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, BR-13083878 Campinas - Brazil

^[10] Univ Fed Parana, Hematol Div, BR-13083878 Curitiba, Parana - Brazil

^[11] Univ Fed Minas Gerais, Hematol Div, BR-30130100 Belo Horizonte, MG - Brazil

^[12] Univ Fed Sao Paulo, Hematol Div, BR-04023062 Sao Paulo - Brazil

^[13] Princess Margaret Canc Ctr, Toronto, ON M5G 2C1 - Canada

^[14] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 - USA

^[15] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 - USA

^[16] Kings Coll London, Sch Med, Dept Med & Mol Genet, London WC2R 2LS - England

^[17] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, D-30625 Hannover - Germany

^[18] Erasmus MC, Dept Hematol, NL-3015 GD Rotterdam - Netherlands

^[19] Univ Tor Vergata, Dept Biopathol, I-00133 Rome - Italy

^[20] Santa Lucia Fdn, I-00179 Rome - Italy

^[21] Hosp Univ Politecn La Fe, Dept Hematol, Valencia 46009 - Spain

^[22] Inst Carlos III, CIBERONC, Madrid 28029 - Spain

^[23] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 - USA

^[24] Univ Fed Pernambuco, Dept Genet, BR-50670901 Recife, PE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 12, n. 11 NOV 2020.
• Citações Web of Science: 1

Resumo

Simple Summary In solid tumors, the altered expression of embryonic genes such as the SLIT-ROBO family has been associated with poor prognosis, while little is known about their role in acute myeloid leukemia (AML). Previous studies reported frequent hypermethylation of SLIT2 mediated by the methyltransferase enzyme EZH2 and more recently the PML protein, which are commonly found to be aberrantly expressed in AML. Here, we aim to assess retrospectively the clinical relevance of the SLIT2 gene in acute promyelocytic leukemia, a homogenous subtype of AML. We demonstrated that reduced SLIT2 expression was associated with high leukocyte counts and reduced overall survival in different APL cohorts. STLI2 treatment decreased APL growth, while SLIT2 knockdown accelerated cell cycle progression and proliferation. Finally, reduced expression of SLIT2 in murine APL blasts resulted in fatal leukemia associated with increased leukocyte counts in vivo. These findings demonstrate that SLIT2 can be considered as a prognostic marker in APL, and a potential candidate for clinical studies of a more heterogeneous disease, such as AML. 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 SLIT2(high) transcript levels were associated with cell cycle arrest, while SLIT2(low) 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. (AU)

• Processo FAPESP: 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante
• Beneficiário: Diego Antonio Pereira Martins
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/09228-0 - Detecção e estudo funcional de Macrofágos Associados a Tumor em um modelo transgênico de leucemia promielocítica aguda.
• Beneficiário: Isabel Weinhauser
• Modalidade de apoio: Bolsas no Brasil - Doutorado