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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1863; no. 2; pp. 450 - 461
• Main Authors: Roversi, Fernanda Marconi, Pericole, Fernando Vieira, Machado-Neto, João Agostinho, da Silva Santos Duarte, Adriana, Longhini, Ana Leda, Corrocher, Flávia Adolfo, Palodetto, Bruna, Ferro, Karla Priscila, Rosa, Renata Giardini, Baratti, Mariana Ozello, Verjovski-Almeida, Sergio, Traina, Fabiola, Molinari, Alessio, Botta, Maurizio, Saad, Sara Teresinha Olalla
• Format: Journal Article
• Language: English
• Published: Netherlands 01-02-2017
• Subjects: Adult; Aged; Cell Death - drug effects; Enzyme Inhibitors - pharmacology; Erythropoiesis - drug effects; Erythropoietin - metabolism; Female; GATA1 Transcription Factor - metabolism; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-hck - antagonists & inhibitors; Proto-Oncogene Proteins c-hck - metabolism; Signal Transduction - drug effects; Young Adult; Hematopoietic cell kinase; Erythroid differentiation; Acute myeloid leukemia; Hematopoietic stem cells; Myelodysplastic syndrome
• ISSN: 0925-4439
• DOI: 10.1016/j.bbadis.2016.11.013

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.