Dennis Garcia-Rhodes

Introduction: Acute myeloid leukemia (AML) arises from hematological diseases where myeloid precursors arrest at different stages within hematopoietic differentiation.¹ AML is the most common type of acute leukemia in adults with an incidence rate of 2.7 per 100,000 population.² Leukemia is screened for using peripheral blood smear, definitively diagnosed with bone marrow biopsy, and frequently treated with combinations of anthracyclines and cytosine arabinoside.² In AML patients, the surface expression of CXCR4 predicts disease relapse and survival.³ Previous studies have demonstrated that upregulating or downregulating SDF-1α/CXCR4 interactions contribute to increased and decreased chemoresistance in leukemia cells, respectively. Overall findings suggest that targeting the SDF-1a/CXCR4 signaling pathway may contribute to less chemoresistance and more effective treatment.³ Methods: Numbers of apoptotic cells were analyzed using propidium iodide binding assays and expressed as percentages of Annexin V-positive cells. Direct volume methods and counting beads assays were used to confirm absolute cell counts. Cellular structures were assessed using electron microscopy. An AML mouse model was utilized, where mice were divided into groups and treated with either phosphate-buffered saline, cytosine arabinoside, an autophagy inhibitor, or a combination. Mice underwent survival analysis and organ collection, where spleen weights were measured as percentages of their body weight. All data underwent statistical analysis. Results: AML cells treated with SDF-1α lead to increased resistance to cytosine arabinoside, indicating the role of CXCR4 in the mediation of cell survival and chemoresistance.³ SDF-1a/CXCR4 interactions increased the amount of autophagosomes in AML cells, proving SDF-1α involvement in regulating autophagy during chemotherapy.³ Significant reduction in viable cell numbers demonstrated that apoptosis induced by cytosine arabinoside is enhanced following inhibition of autophagy in AML cells.³ In a systemic mouse model, the combined use of an autophagy inhibitor and cytosine arabinoside improved overall survival time compared to treatment with either method individually.³ Conclusion: Patients with AML can typically expect high rates of complete remission, yet there is still the need for the development of novel long term relapse therapy, as some patients still experience complications from treatment.⁴ Several studies have discovered that upregulating CXCR4 signaling increases autophagic activity and decreases apoptosis in AML cells.³ With a primary focus on inhibitors and blocking antibodies, the SDF-1a/CXCR4 axis is a promising therapeutic target in AML to reduce the enhanced survival and proliferation of leukemic cells.⁴ Understanding the SDF1a/CXCR4 axis can improve remission in AML and further our understanding of other immunologic diseases. This novel finding warrants further research.

1. Moosavi MA, Djavaheri-Mergny M. Autophagy: New insights into mechanisms of action and resistance of treatment in acute promyelocytic leukemia. International journal of molecular sciences. 2019;20(14):3559. https://www.ncbi.nlm.nih.gov/pubmed/31330838. doi: 10.3390/ijms20143559.
2. Rose-Inman H, Kuehl D. Acute leukemia. Hematology/Oncology Clinics of North America. 2017;31(6):1011-1028. http://www.sciencedirect.com.srv-proxy1.library.tamu.edu/science/article/pii/S0889858817301302. doi: https://doi-org.srv-proxy1.library.tamu.edu/10.1016/j.hoc.2017.08.006 “.
3. Hu X, Mei S, Meng W, et al. CXCR4-mediated signaling regulates autophagy and influences acute myeloid leukemia cell survival and drug resistance. Cancer Letters. 2018;425:1-12. http://www.sciencedirect.com.srv-proxy1.library.tamu.edu/science/article/pii/S0304383518302210. doi: https://doi-org.srv-proxy1.library.tamu.edu/10.1016/j.canlet.2018.03.024.
4. Landry B, Gül-Uludağ H, Plianwong S, et al. Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia. Journal of Controlled Release. 2016;224:8-21. http://dx.doi.org/10.1016/j.jconrel.2015.12.052. doi: 10.1016/j.jconrel.2015.12.052.