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

Abstract

The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy resistance. In acute myeloid leukemia (AML), leukemic stem/progenitor cells (LSC) anchored in the protective BM microenvironment, reprogram and transform this niche into a leukemia-supporting and chemoprotective environment. One most important player involved in this crosstalk are CXCL12, produced by the BM mesenchymal stromal cells, and its receptor CXCR4, present onto HSC. The downstream molecular mechanisms involved in CXCL12/CXCR4 axis have many targets, including the Src family members of non-receptor tyrosine kinase (SFK). We herein study the role of one SFK member, the Hematopoietic Cell Kinase (HCK), in CXCL12/CXCR4 pathway and its contribution to the AML pathogenesis. We verified that the inhibition of HCK severely impaired CXCL12-induced migration of leukemic cell lines and CD34 positive cells from AML patients bone marrow, through a disruption of the activation of CXCL12/CXCR4/PI3K/AKT and CXCL12/CXCR4/MAPK/ERK signaling, and by a decreased cytoskeleton dynamic through a lower rate of actin polymerization. We provide new insights into the key role of HCK in conferring a migratory advantage to leukemic cells thought CXCL12/CXCR4 axis. HCK represents an important protein of the main pathway involved in the crosstalk between HSC, and their surrounding milieu. Thus, HCK inhibition could represent a novel approach for the treatment of the acute myeloid leukemia.

Understanding the interaction between leukaemia stem cells and their microenvironment to improve therapeutic approaches

“…CXCL12 attracts HSCs expressing its cognate receptor [C-X-C chemokine receptor (CXCR4)] (Roversi et al, 2021). CXCL12-CXCR4 signalling is involved in homing of normal HSCs/HSPCs, as well as LSCs, into BM (Kim & Broxmeyer, 1998;Roversi et al, 2021). Therefore, aberrant expression of CXCR4 by LSCs or targeting CXCL12 affects the homing process (Jin et al, 2008).…”

“…In addition to osteoblasts and Nestin + MSCs, CAR cells produce high levels of CXCL12, also known as stromal cell‐derived factor‐1 (SDF‐1) (Cordeiro Gomes et al, 2016). CXCL12 attracts HSCs expressing its cognate receptor [C‐X‐C chemokine receptor (CXCR4)] (Roversi et al, 2021). CXCL12‐CXCR4 signalling is involved in homing of normal HSCs/HSPCs, as well as LSCs, into BM (Kim & Broxmeyer, 1998; Roversi et al, 2021).…”

“…CXCL12 attracts HSCs expressing its cognate receptor [C‐X‐C chemokine receptor (CXCR4)] (Roversi et al, 2021). CXCL12‐CXCR4 signalling is involved in homing of normal HSCs/HSPCs, as well as LSCs, into BM (Kim & Broxmeyer, 1998; Roversi et al, 2021). Therefore, aberrant expression of CXCR4 by LSCs or targeting CXCL12 affects the homing process (Jin et al, 2008).…”

Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells

“…Many cytokines secreted by tumor cells can recruit macrophages to the TME, but some of them are exclusively produced by CSCs: CCL2, CCL3, CCL5, CXC motif chemokine ligand 12 (CXCL12), olfactomedin-like 3 (OLFML3), stromal-cell-derived factor-1b (Sdf1b), IL-6, IL-33, and CSF-1 [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] ( Figure 1 ). CSCs contribute to the infiltration of macrophages or microglia to promote their own metastatic spread [ 38 , 39 , 43 , 46 ].…”

The Prognosis Risk Model Based on Immune-related Genes Is Closely Related to the Prognosis of Oral Cancer

“…The increase in HCK activity has also been observed in a number of solid malignancies, including breast and colon cancers, and is associated with worse patient survival [9,10]. The excessive activation of HCKs may be caused by the stimulation of tumor cells by cytokines secreted from peripheral immune cells, thus enhancing tumor activation and promoting TME formation [11]. The overexpression of periostin (POSTN) is positively correlated with gastric cancer metastasis by promoting tumor metastasis and invasion [12].…”