title: 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: HCK in erythropoietin/PI3K pathway.
abstract: 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.
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fernanda Marconi
authors.initials: FM
authors.lastname: Roversi
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fernando Vieira
authors.initials: FV
authors.lastname: Pericole
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: João Agostinho
authors.initials: JA
authors.lastname: Machado-Neto
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: da Silva Santos Duarte
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Ana Leda
authors.initials: AL
authors.lastname: Longhini
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Flávia Adolfo
authors.initials: FA
authors.lastname: Corrocher
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Palodetto
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Karla Priscila
authors.initials: KP
authors.lastname: Ferro
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Renata Giardini
authors.initials: RG
authors.lastname: Rosa
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Mariana Ozello
authors.initials: MO
authors.lastname: Baratti
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Verjovski-Almeida
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Molinari
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil. Electronic address: sara@unicamp.br.
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
mesh_terms: D000328:Adult; D000368:Aged; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D050982:GATA1 Transcription Factor; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck
keywords: Acute myeloid leukemia; Erythroid differentiation; Hematopoietic cell kinase; Hematopoietic stem cells; Myelodysplastic syndrome