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

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.

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia

“…Finally, inhibition of another FLT3 downstream pathway [ 8 , 45 , 49 ], the PI3K-Akt signaling pathway, reverses resistance of T-ALL [52] and MLL-ALL [19] cells to GCs. Inhibition of HCK reduces the PI3K-Akt, but also the MAPK signaling pathway, in cells with upregulated HCK expression and thereby HCK becomes a potential drug target in leukaemia [53] . Taken together, SFK and FLT3 signaling seems to drive MLL-ALL via several pathways which are cooperatively involved in GC-resistance.…”

­­Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

“…HCK is an important member of the receptor tyrosine protein kinase family and is expressed in myeloid monocytes and B lymphocytes [24].…”

Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis

“…To confirm the involvement of HCK in CXCL12/CXCR4 axis, we tested a new selective HCK inhibitor, called iHCK-37, synthesized by Dr. Maurizio Botta (in memoriam) (Tintori et al, 2013). The inhibition of 50% growth (GI 50 ) of KG1a and U937 cells, induced by iHCK-37, was previously determined by us (Roversi et al, 2017). KG1a and U937 cells were pretreated with different doses of iHCK-37 for 48 h (3, 6, and 9 µM corresponding, respectively, to half of GI50, to GI50 and to two times GI50) and then subjected to Transwell-based migration assays in the presence or absence of a stimulus, CXCL12, for an additional 24 h. The iHCK-37 pretreatment in the three tested doses significantly reduced CXCL12-induced cell chemotaxis (KG1a cells: average 2.9%, range 2.5-3.5%, and U937 cells: average 2.0%, range 0.5-3.6%) compared to vehicle treated cells (KG1a cells: average 21.2%, range 19.4-23.3%, and U937 cells: average 33.3%, range 50.8-57.5%; P < 0.01, Figure 3A).…”

“…Deregulation of SFK is frequently observed in diverse human cancer and its upregulation has been associated with poor clinical prognosis and tumor recurrence (Dubois et al, 2015). Interestingly, our group identified high expression of a SFK member, the hematopoietic cell kinase (HCK), in primary CD34 positive hematopoietic cells isolated from myelodysplastic syndrome (MDS) patients bone marrow (Roversi et al, 2017) and from de novo AML patients bone marrow (Baratti et al, 2010), a clonal hematopoietic stem cell disorder with a risk of 30% to progress toward AML (Chen et al, 2019).…”