STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells

Author(s):Show less -

Vicari, Hugo Passos ^[1] ; Coelho-Silva, Juan Luiz ^[2] ; Pereira-Martins, Diego A. ^{[2, 3]} ; Lucena-Araujo, Antonio Roberto ^[4] ; Lima, Keli ^[3] ; Lipreri da Silva, Jean Carlos ^[1] ; Scheucher, Priscila Santos ^[2] ; Koury, Luisa C. ^[2] ; de Melo, Raul A. ^{[5, 6]} ; Bittencourt, Rosane ^[7] ; Pagnano, Katia ^[8] ; Nunes, Elenaide ^[9] ; Fagundes, Evandro M. ^[10] ; Kerbauy, Fabio ^[11] ; De Figueiredo-Pontes, Lorena Lobo ^[2] ; Costa-Lotufo, Leticia Veras ^[1] ; Rego, Eduardo Magalhaes ^[3] ; Traina, Fabiola ^[2] ; Machado-Neto, Joao Agostinho ^[1]

Affiliation:Show less -

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med Imaging Hematol & Oncol, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Dept Hematol, Lab Med Invest Pathogenesis & Target, Sao Paulo - Brazil

^[4] Univ Fed Pernambuco, Dept Genet, Recife, PE - Brazil

^[5] Fundacao HEMOPE, Recife, PE - Brazil

^[6] Univ Pernambuco, Dept Internal Med, Recife, PE - Brazil

^[7] Univ Fed Rio Grande do Sul, Univ Hosp, Hematol Div, Porto Alegre, RS - Brazil

^[8] Univ Estadual Campinas, Hemoctr Unicamp, Campinas - Brazil

^[9] Univ Fed Parana, Hematol Div, Curitiba, Parana - Brazil

^[10] Univ Fed Minas Gerais, Hematol Div, Belo Horizonte, MG - Brazil

^[11] Univ Fed Sao Paulo, Hematol Div, Sao Paulo - Brazil

• Document type: Journal article
• Source: INVESTIGATIONAL NEW DRUGS; NOV 2021.
• Web of Science Citations: 0

Abstract

Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML-RAR alpha fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p< 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p< 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL. (AU)

• FAPESP's process: 19/01700-2 - Functional investigation of Stathmin 1 in proliferation, differentiation and apoptosis in acute promyelocytic leukemia model
• Grantee: Hugo Passos Vicari
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/12842-0 - Impact of genetic ancestry on development, molecular characteristics and clinical outcome in adult patients with Acute Lymphoblastic Leukemia
• Grantee: Keli Cristina de Lima
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model
• Grantee: Diego Antonio Pereira Martins
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/24993-0 - Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants