A Perfused Liver Module Separates AML-Associated Injury from Direct Leukemia Killing

Reconstructing a Diseased Drug-Exposure Environment

Chemotherapy acts on tissues already altered by the disease it treats. A Science Advances study from the Chinese Academy of Medical Sciences and Peking Union Medical College combined human liver cells, a perfused vascular network and cells from patients with acute myeloid leukemia. The investigators used this DPHV–liver module to study leukemic infiltration and liver injury during cytarabine exposure.

The construct contained expanded primary human hepatocytes, termed ProliHHs, and human umbilical-vein endothelial cells. Its hepatic matrix included decellularized liver material. Bone-marrow mononuclear cells from three AML donors supplied the disease component: one sample was used for the infiltration time course, with two further samples providing additional comparisons. The model maintained its structure and selected functions for seven days.

Perfusion Supported Liver Function and an Infiltration Assay

Compared with static three-dimensional culture, perfusion improved albumin-related measurements and CYP1A2 and CYP3A4 activity. These endpoints established a functional baseline before adding leukemia cells and drugs. Hydrogel composition also affected survival and function, showing that the engineering conditions contributed to the biological state of the construct.

Patient-derived AML cells entered the liver compartment over a time course extending to 360 minutes. Cytarabine challenge then allowed the team to examine hepatic injury and leukemia behavior together. Drug comparisons used 12-hour exposure and included several candidate hepatoprotective agents.

Ammonium Glycyrrhizinate Had a Context-Dependent Effect

Ammonium glycyrrhizinate, abbreviated AMGZ, preserved hepatocyte viability and albumin-related function during cytarabine treatment, reduced caspase-3-associated injury and decreased hepatic leukemic infiltration. Schisandrin, bicyclol and silymarin showed little protection in the reported screen. Follow-up chloroquine and ferrostatin-1 conditions also produced limited or negligible benefit.

AMGZ alone did not significantly increase apoptosis in isolated primary AML cells or reduce their migration and invasion. The protective and anti-infiltration effects therefore depended on the liver-associated experimental context. The results do not support describing AMGZ as a directly cytotoxic AML drug.

Single-cell analysis resolved eight hepatic and hematopoietic subpopulations. The combination was associated with reduced hepatocyte expression of cytidine deaminase, an enzyme involved in cytarabine metabolism. The authors proposed that this could stabilize cytarabine locally. Local drug concentrations and metabolic flux were not directly measured, leaving that explanation as a mechanistic hypothesis.

Mouse and Retrospective Patient Data Supplied Different Checks

In patient-derived xenograft mice, adding AMGZ to cytarabine reduced liver leukemic burden and improved liver-injury markers. Extrahepatic disease burden was not reduced relative to high-dose cytarabine, and overall survival was not significantly prolonged. The hepatic benefit therefore did not translate into a demonstrated systemic survival advantage in that experiment.

The paper also examined a retrospective single-center AML cohort of 422 patients. A subset of 326 with normal baseline liver function was used to assess injury associated with cytarabine, while serial markers were examined in 313 patients who received cytarabine plus AMGZ. Improvements in liver-related measurements were qualitatively consistent with the model findings.

These clinical observations were not a randomized comparison. Regimens and treatment timing varied, and spontaneous recovery lacked a suitable control. The cohort did not establish that a construct derived from an individual patient predicted that patient’s outcome. It provided a separate clinical association around the same liver-injury question.

The Model’s Reach Is Defined by Its Compartments and Duration

The module makes a useful distinction between hepatocyte injury, local leukemic infiltration and direct leukemia-cell killing. Those outcomes changed differently in the same study. Its seven-day window and simplified, unidirectional vasculature leave chronic injury and full sinusoidal biology outside the demonstrated scope. Kupffer and stellate cells were also absent, limiting inflammatory and fibrotic responses. The work supports further liver-context testing of candidate combinations, with systemic benefit and patient-level prediction still to be established.