What Is the Role of MS4A3 in Chronic-Phase Chronic Myeloid Leukemia?

Take-aways

• In chronic-phase chronic myeloid leukemia (CP-CML), low MS4A3 is a common mechanism in CML stem/progenitor cell inactivity, BCR-ABL1-independent primary tyrosine kinase inhibitor resistance, and blastic transformation.
• MS4A3 regulates βc receptor endocytosis and signaling, thus controlling LSPC sensitivity to differentiating cytokines.
• According to these findings, enhancing MS4A3 levels may represent a potential treatment strategy for resistant/intolerant CP-CML.

A recent study published in Blood found that downregulation of MS4A3 contributes to disease progression and BCR-ABL inhibitor resistance in chronic-phase chronic myeloid leukemia (CP-CML).

CP-CML is characterized by excessive production of maturing myeloid cells. Like normal hematopoiesis under stress, CML stem/progenitor cells (LSPCs) must balance conservation and differentiation. Because BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells while sparing BCR-ABL1–independent LSPCs, “understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs,” wrote the study authors, led by Helong Zhao, PhD, of the University of Utah School of Medicine.

The investigators performed a meta-analysis of published CML transcriptomes and found that low expression of the MS4A3 transmembrane protein was universal in LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase.

Previous studies have suggested that MS4A3 functions as a G1/S phase inhibitor. However, Dr. Zhao and colleagues discovered that MS4A3 promotes endocytosis of common β-chain cytokine receptors upon GM-CSF/IL-3 simulation, enhancing downstream signaling and cellular differentiation.

“This suggests that LSPCs downregulate MS4A3 to evade β-chain cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state,” the authors wrote.

Based on their findings, a model in which MS4A3 governs response to differentiating myeloid cytokines may provide a unifying mechanism for the differentiation block characteristic of CML inactivity and blast-phase CML. In addition, encouraging MS4A3 re-expression, or delivering ectopic MS4A3, may help to kill LSPCs in vivo.

“Based on this work, some interesting questions are worthy of further studies,” Kaosheng Lv and Wei Tong, PhD, of the Children’s Hospital of Philadelphia, wrote in a related editorial published in Blood. “Does MS4A3 play a role in other myeloid malignancies? Does MS4A3 anchor common βc receptors to specific membrane microdomains, such as a lipid raft or lysosomes that could affect receptor turnover? What are the additional targets of MS4A3?”

According to Dr. Lv, further research is required to develop new therapies to promote MS4A3 expression and, in combination with TKIs, eradicate CML LSPCs. Additionally, therapies utilizing targeted delivery of MS4A3 may lead to deeper molecular responses in patients with CP-CML receiving TKIs.

Disclosures: This research was supported in part by the National Institutes of Health and National Cancer Institute. Study authors report no relevant conflicts of interest.

References

1. Zhao H, Pomicter AD, Eiring AM, et al. MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis. Blood. 2022;139(5):761-778.
2. Lv K, Tong W. Waking up CML leukemia stem cells for the kill. Blood. 2022;139(5):647-648.