Hematopoietic cell kinase (HCK) is a potential therapeutic target for dysplastic and leukemic cells due to integration of erythropoietin/PI3K pathway and regulation of erythropoiesis

Autor: Alessio Molinari, Flávia Adolfo Corrocher, Bruna Palodetto, Sara Teresinha Olalla Saad, Mariana Ozello Baratti, Maurizio Botta, Fabiola Traina, Fernando V Pericole, Adriana S. S. Duarte, Fernanda Marconi Roversi, João Agostinho Machado-Neto, Sergio Verjovski-Almeida, Karla Priscila Ferro, Renata Giardini Rosa, Ana Leda F. Longhini
Rok vydání: 2017
Předmět:
Zdroj: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863:450-461
ISSN: 0925-4439
DOI: 10.1016/j.bbadis.2016.11.013
Popis: New drug development for neoplasm treatment is nowadays based on molecular targets that participate in the disease pathogenesis and tumor phenotype. Herein, we describe a new specific pharmacological hematopoietic cell kinase (HCK) inhibitor (iHCK-37) that was able to reduce PI3K/AKT and MAPK/ERK pathways activation after erythropoietin induction in cells with high HCK expression: iHCK-37 treatment increased leukemic cells death and, very importantly, did not affect normal hematopoietic stem cells. We also present evidence that HCK, one of Src kinase family (SFK) member, regulates early-stage erythroid cell differentiation by acting as an upstream target of a frequently deregulated pathway in hematologic neoplasms, PI3K/AKT and MAPK/ERK. Notably, HCK levels were highly increased in stem cells from patients with some diseases, as Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML), that are associated with ineffective erythropoiesis These discoveries support the exploration of the new pharmacological iHCK-37 in future preclinical and clinical studies.
Databáze: OpenAIRE
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