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

Fernanda Marconi Roversi,Fernando Viera Pericole,Sara Teresinha Olalla Saad,Maura Lima Pereira Bueno

doi:10.3389/fcell.2021.634044

Fernanda Marconi Roversi, Fernando Viera Pericole + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2021.634044

Copy DOI

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.

Highlights

Acute myeloid leukemia (AML), the most common acute leukemia in older adults (60 years of age or over), is characterized by an uncontrolled myeloid cell expansion, resulting in an impaired capacity to differentiate into fully mature cells that could culminate in bone marrow failure (BM) (Siveen et al, 2017; El-Jawahri et al, 2019)
In order to investigate the role of Hematopoietic Cell Kinase (HCK) on CXCL12/CXCR4 axis in leukemia cells, two human myeloid leukemia cell lineages, the U937 (AML CD34 negative cells) and the KG1a (AML CD34 positive cells) were stably transduced with lentivirus-mediated shRNA targeting HCK gene or an appropriate control
The crosstalk between leukemic stem/progenitor cells and bone marrow microenvironment has been highlighted as an important process for the resistance to chemotherapy and disease relapse in AML, mainly through the activation of the CXCL12/CXCR4 pathway (Bernasconi and Borsani, 2019)

Summary

Introduction

Acute myeloid leukemia (AML), the most common acute leukemia in older adults (60 years of age or over), is characterized by an uncontrolled myeloid cell expansion, resulting in an impaired capacity to differentiate into fully mature cells that could culminate in bone marrow failure (BM) (Siveen et al, 2017; El-Jawahri et al, 2019). During normal hematopoietic stem/progenitor cell (HSC) differentiation, some genetic mutations can occur, leading to a clonal evolution and leukemic stem/progenitor cell (LSC) formation. These malignant cells are able to use the neighboring bone marrow microenvironment (niche) for their expansion, self-renewal, and survival, without being recognized, inducing leukemic progression. This crosstalk between LSC and the BM niche is an important mediator of chemotherapy resistance, and disease relapse (Ladikou et al, 2020). High CXCR4 gene expression or protein activation into AML CD34 positive blasts is known to be associated with poor prognosis of AML patients (Du et al, 2019)

Methods

Results

Conclusion