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Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.
And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.
The researchers reported these findings in Cancer Cell.
“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.
This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.
Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.
This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.
With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.
They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.
The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.
Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.
Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.
The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL. 
Photo by Rhoda Baer
Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.
And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.
The researchers reported these findings in Cancer Cell.
“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.
This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.
Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.
This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.
With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.
They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.
The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.
Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.
Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.
The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL.
Photo by Rhoda Baer
Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.
And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.
The researchers reported these findings in Cancer Cell.
“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.
This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.
Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.
This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.
With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.
They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.
The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.
Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.
Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.
The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL.