Newly identified enzyme protects growth protein in leukemia cells

A research team has identified an enzyme that helps acute myeloid leukemia (AML) cells survive by protecting c-MYC, a protein that drives cell growth, from degradation. The enzyme, known as protein tyrosine phosphatase non-receptor type 2 (PTPN2), removes a phosphate group that helps mark c-MYC for breakdown. Reducing PTPN2 levels slowed leukemia cell growth and increased programmed cell death in laboratory experiments, while an experimental compound that inhibits the enzyme slowed the growth of human leukemia cell implants in mice. The findings point to a potential way to weaken c-MYC-driven growth and provide a starting point for developing more selective inhibitors.

AML develops when immature blood-forming cells accumulate and crowd out healthy cells in the bone marrow. Chemotherapy remains a mainstay of treatment, and targeted medicines such as venetoclax have expanded the options available to patients. Drug resistance and treatment-related toxicity, however, continue to complicate care. Previous research had linked PTPN2 to immune signaling and shown that its effects can differ across cancers. Earlier analyses also indicated that the gene encoding PTPN2 was more active in AML samples. What remained unclear was whether leukemia cells depended on the enzyme for growth and which proteins might account for that dependence.

A study (DOI: 10.48130/targetome-0026-0052) published in Targetome on 16 October 2026 by Peng Yang's team, China Pharmaceutical University, reports that PTPN2 stabilizes c-MYC and that disrupting this process curbs leukemia cell growth in preclinical models.

The team first analyzed public gene expression and survival datasets, finding that PTPN2 expression was higher in AML samples than in controls and that patients with higher expression tended to have shorter overall survival. Laboratory measurements of patient samples also found elevated levels of both PTPN2 messenger RNA and PTPN2 protein. To test whether leukemia cells depended on the enzyme, the researchers reduced its production in patient-derived cells and in two human leukemia cell lines, MOLM13 and NB4. More cells stopped in G1, the stage before DNA replication, and underwent programmed cell death. Restoring active PTPN2 rescued growth in both cell lines, while an inactive version of the enzyme failed to do so.

RNA sequencing of MOLM13 cells showed that reducing PTPN2 lowered the activity of gene sets regulated by c-MYC. The team then used mass spectrometry to look for proteins that bound to PTPN2 and gained phosphate groups when the enzyme was depleted. c-MYC met both criteria. In assays with purified proteins, active PTPN2 removed a phosphate group from c-MYC at threonine 58, a site involved in marking the protein for degradation. Follow-up experiments showed that c-MYC broke down faster when PTPN2 levels fell and that restoring c-MYC helped MOLM13 cells resume growth. The team then tested WS35, a small molecule that inhibits PTPN2, in both leukemia cell lines. The compound increased phosphorylation at threonine 58, lowered c-MYC protein levels, and reproduced the cell-cycle arrest and rise in cell death seen after PTPN2 depletion. In mice implanted with NB4 cells, WS35 slowed tumor growth, with no significant change in body weight during the experiment. Tumor samples from treated mice also contained less c-MYC and showed fewer signs of cell proliferation.

The study links PTPN2 activity to the persistence of c-MYC in leukemia cells and shows that an experimental inhibitor can disrupt that process. WS35 also inhibits the closely related enzyme PTP1B, so developing compounds that distinguish between the two enzymes will help clarify how much of the effect comes from blocking PTPN2. Further preclinical studies will need to assess whether the approach works in models that more closely reflect how AML develops in the bone marrow.