Dataset Information

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

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-Ch17’s 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 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. In addition, we identified ATP Synthase subunits as binding partners of PAMD-Ch17 and showed that the polymer, but not AMD3100, inhibited ATP Synthase activity. 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 patient 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: R. Katherine Hyde

LAB HEAD: R. Katherine Hyde

PROVIDER: PXD066096 | Pride | 2026-02-16

REPOSITORIES: Pride

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			Action	DRS
	20240923_CL_A.raw	Raw
	20240923_CL_A__F023680_.mzid	Mzid
	20240923_CL_A__F023680_.mzid_20240923_CL_A__F023680_.MGF	Mzid
	20240923_CL_B.raw	Raw
	20240923_CL_B__F023681_.mzid	Mzid

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Publications

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

Lam Calvin C Dhir Arjun A Jogdeo Chinmay M CM Panda Sipra S Kapoor Ekta E Tang Siyuan S Rivero Victor V McIntyre Erin M EM Coulter Donald W DW Xiao Peng P Black Adrian R AR Hewitt Kyle K Swenson Samantha A SA Romanova Svetlana S Oupicky David D Hyde R Katherine RK

bioRxiv : the preprint server for biology 20250601

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-Ch17's 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 sensi ...[more]

PMID: 40501752

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Project description:Nucleotides triphosphates are extracellular messengers binding to specific plasma membrane receptors (P2Rs) that modulate responses as different as proliferation, differentiation, migration or cell death on several cell types including hematopoietic stem cells. Little and controversial information is available on the role of extracellular nucleotides in human mesenchimal stem cells (hMSCs). In this study, we assessed whether P2Rs are expressed and functional in bone marrow-derived hMSCs. Our results demonstrated, at the mRNA and protein level, the expression of all P2X and P2Y receptor subtypes identified so far. P2R activation by their natural ligands adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced in hMSCs, intracellular Ca2+ concentration changes, plasma membrane depolarization and permeabilization. hMSCs were resistant to the cytotoxic effects of high dose ATP despite the expression of permeabilizing P2Rs as demonstrated by the lack of morphological changes, significant release of intracellular markers of cell death or modification of the mitochondrial network. Gene expression profiling revealed the down-regulation of cell proliferation genes whereas genes involved in cell migration and cytokine production were strongly up-regulated by ATP. Functional studies confirmed the inhibitory activity of ATP on proliferation of hMSCs and clonogenic progenitors. Moreover, ATP exerted a chemotactic effect on hMSCs and increased their migration in response to the chemokine CXCL12. Finally, whereas ATP did not affect T-cell inhibitory activity of hMSCs, the nucleotide increased the production of pro-inflammatory cytokines by hMSCs. Thus, our data show that purinergic signaling modulates hMSC functions and point to a role for extracellular nucleotides on hMSCs biology. hMSCs from 6 healthy donors were seeded at a density of 2.5 x 103 cells/cm2 for 24 hours with or without 1mM ATP. We then assessed the transcriptome profile of ATPM-bM-^@M-^Streated and untreated cells using Affymetrix HG-U133 Plus 2 GeneChip array.