PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4

Lam, C.; Dhir, A.; Jogdeo, C. M.; Panda, S.; Kapoor, E.; Tang, S.; Rivero, V.; McIntyre, E. M.; Xiao, P.; Black, A. R.; Hewitt, K.; Swenson, S. A.; Romanova, S.; Oupicky, D.; Hyde, R. K.

doi:10.1101/2025.05.28.656643

bioRxiv · 10.1101/2025.05.28.656643

PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4

Lam, C.·Dhir, A.·Jogdeo, C. M.·Panda, S.·Kapoor, E.·Tang, S.·Rivero, V.·McIntyre, E. M.·Xiao, P.·Black, A. R.·Hewitt, K.·Swenson, S. A.·Romanova, S.·Oupicky, D.·Hyde, R. K.

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Abstract

PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse Acute Myeloid Leukemia cells. To investigate the mechanism of PAMD-Ch17s novel anti-leukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-ALL cell lines being highly sensitive. Surprisingly, CXCR4 knock out T-ALL cells were equally sensitive to PAMD-Ch17. Using a fluorescently tagged PAMD-Ch17, we found that the drug colocalized to the mitochondria. We also found that PAMD-Ch17 induced changes in expression of genes related to mitochondrial function, increased levels of mitochondrial superoxide, and decreased mitochondrial membrane potential. Using seahorse assays, we found that PAMD-Ch17 decreased baseline oxygen consumption, ATP production, and proton leakage. PAMD-Ch17 also decreased baseline extracellular acidification rate, indicating a decrease in overall metabolism. In mouse primary T-ALL but not healthy bone marrow cells, PAMD-Ch17 induced both mitochondrial superoxide and cell death. Using human bone marrow organoids, we found that PAMD-Ch17 induced mitochondrial superoxide and cell death in human primary T-ALL cells, but not in healthy stromal and hematopoietic cells. Collectively, our results indicate that PAMD-Ch17 has anti-leukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4 independent, mitochondrial based mechanism. These findings support further development of PAMDs as potential therapeutics for patients with T-ALL. KEY POINTSO_LIPAMD-Ch17, a polymeric drug based on AMD3100/Plerixafor, has novel anti-leukemic activities against T-ALL that are independent of CXCR4 inhibition. C_LIO_LIPAMD-Ch17 induces increased mitochondrial superoxide and cell death in primary ALL cells, but not healthy bone marrow cells. C_LI

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Lam, C., Dhir, A., Jogdeo, C. M., Panda, S., Kapoor, E., Tang, S., Rivero, V., McIntyre, E. M., Xiao, P., Black, A. R., Hewitt, K., Swenson, S. A., Romanova, S., Oupicky, D., Hyde, R. K.. 2025-06-01. PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4. https://doi.org/10.1101/2025.05.28.656643

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