Contributions
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:00 to 14.06.2015 08:15
Location: Room Stolz 1
Background
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from the leukemic transformation of T-cell progenitors. Despite progress in intensive chemotherapy, 25% of pediatric and over 50% of adult patients with T-ALL show resistance to therapy and relapse. The pathophysiology of T-ALL suggests a significant deregulation of cell migration and tissue infiltration. Previously we showed that the serin-threonin protein phosphatase Calcineurin (Cn) regulates the physical and functional interaction that T-ALL cells establish with other cells in the tumor microenvironment, notably their adhesive and migratory properties, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation and ultimately inhibition of Leukemia Initiating Cell (LIC) activity (Gachet et al., 2013).
Aims
The aim of this study is to dissect the molecular mechanisms underlying the interactions between T-ALL cells and their microenvironment which are perturbed by Cn inactivation, and explore their therapeutic importance.
Methods
NOTCH-induced murine T-ALL in which Cn can be genetically inactivated were used to study the effect of Cn deletion on leukemic cells migration on stromal cells and on CXCR4 recycling. Retroviral mediated transduction of T-ALL cells was used to perform rescue experiments with both CXCR4 and Cortactin (Cttn). In vivo syngeneic transplantation studies were performed to analyse LIC activity of T-ALL cells, and two-photon confocal microscopy to study their homing ability. Sh-RNA lentiviral transduction of T-ALL cells was used to study the effect of CXCR4 knock-down on murine and human T-ALL.
Results
We identify CXCL12/CXCR4 as a highly deregulated pathway in T-ALL upon Cn deletion. Indeed, we demonstrate that Cn has a central role in CXCL12 signaling by regulating CXCR4 recycling at the cell surface. Farther, we link regulation of CXCR4 cell surface expression and CXCL12 responsiveness to the Cn-dependent expression of the actin binding protein Cttn in T-ALL. Moreover, we demonstrate that CXCL12/CXCR4 pathway not only regulates T-ALL migratory properties, but also their survival and proliferation ex vivo, and their homing and LIC activity in vivo both in NOTCH-induced mouse T-ALL and in human T-ALL xenografts.
Summary
Our results reveal a Cn-dependent regulation of CXCR4 surface expression and signaling, which plays a fundamental role in T-ALL migration. Moreover, our findings identify CXCR4 as an important regulator of T-ALL homing and transplantation and call for clinical trials targeting the calcineurin-CXCR4 axis to interfere with leukemogenesis and to improve current chemotherapy regimens in T-ALL.
Session topic: Towards targeted therapy in ALL
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:00 to 14.06.2015 08:15
Location: Room Stolz 1
Background
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from the leukemic transformation of T-cell progenitors. Despite progress in intensive chemotherapy, 25% of pediatric and over 50% of adult patients with T-ALL show resistance to therapy and relapse. The pathophysiology of T-ALL suggests a significant deregulation of cell migration and tissue infiltration. Previously we showed that the serin-threonin protein phosphatase Calcineurin (Cn) regulates the physical and functional interaction that T-ALL cells establish with other cells in the tumor microenvironment, notably their adhesive and migratory properties, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation and ultimately inhibition of Leukemia Initiating Cell (LIC) activity (Gachet et al., 2013).
Aims
The aim of this study is to dissect the molecular mechanisms underlying the interactions between T-ALL cells and their microenvironment which are perturbed by Cn inactivation, and explore their therapeutic importance.
Methods
NOTCH-induced murine T-ALL in which Cn can be genetically inactivated were used to study the effect of Cn deletion on leukemic cells migration on stromal cells and on CXCR4 recycling. Retroviral mediated transduction of T-ALL cells was used to perform rescue experiments with both CXCR4 and Cortactin (Cttn). In vivo syngeneic transplantation studies were performed to analyse LIC activity of T-ALL cells, and two-photon confocal microscopy to study their homing ability. Sh-RNA lentiviral transduction of T-ALL cells was used to study the effect of CXCR4 knock-down on murine and human T-ALL.
Results
We identify CXCL12/CXCR4 as a highly deregulated pathway in T-ALL upon Cn deletion. Indeed, we demonstrate that Cn has a central role in CXCL12 signaling by regulating CXCR4 recycling at the cell surface. Farther, we link regulation of CXCR4 cell surface expression and CXCL12 responsiveness to the Cn-dependent expression of the actin binding protein Cttn in T-ALL. Moreover, we demonstrate that CXCL12/CXCR4 pathway not only regulates T-ALL migratory properties, but also their survival and proliferation ex vivo, and their homing and LIC activity in vivo both in NOTCH-induced mouse T-ALL and in human T-ALL xenografts.
Summary
Our results reveal a Cn-dependent regulation of CXCR4 surface expression and signaling, which plays a fundamental role in T-ALL migration. Moreover, our findings identify CXCR4 as an important regulator of T-ALL homing and transplantation and call for clinical trials targeting the calcineurin-CXCR4 axis to interfere with leukemogenesis and to improve current chemotherapy regimens in T-ALL.
Session topic: Towards targeted therapy in ALL