Leukocyte Receptor Tyrosine Kinase is A Novel Therapeutic Target In B-Cell Acute Lymphoblastic Leukemia.

Abstract

Introduction: B-cell acute lymphoblastic leukemia (B-ALL) is associated with a poor prognosis, highlighting the need for novel therapeutic targets. Leukocyte receptor tyrosine kinase (LTK) is aberrantly activated in solid tumors; however, its role in B-ALL remains unclear. This study aimed to investigate the expression, functional significance, and therapeutic potential of LTK in B-ALL.

Methods: LTK expression and its prognostic value were analyzed using public databases. Validation was performed on peripheral blood mononuclear cells from 17 B-ALL patients and 8 healthy donors via qRT-PCR and Western blot. Functional studies involved LTK knockdown via shRNA in the Nalm-6 B-ALL cell line, assessing proliferation, colony formation, and cell cycle progression in vitro, and tumor growth and infiltration in NOG mouse xenografts. The effects of lorlatinib on cell viability, PI3K/AKT signaling, MAPK/ERK signaling, and synergy with prednisone were evaluated using CCK-8 assays, Western blot, and combination index analysis.

Results: LTK mRNA and protein levels were significantly elevated in B-ALL patients. Analysis of TARGET databases revealed a significant association between high LTK expression and shorter overall survival. LTK knockdown suppressed Nalm-6 cell proliferation, colony formation, and G1/S phase progression in vitro, extended survival in xenograft models, and reduced leukemic infiltration in bone marrow, peripheral blood, spleen, and liver. Lorlatinib inhibited Nalm-6 cell viability, downregulated phospho-AKT and phospho-ERK, and demonstrated synergistic cytotoxicity with prednisone.

Conclusion: LTK is overexpressed in B-ALL and drives disease pathogenesis. Targeting LTK with lorlatinib, alone or in combination with prednisone, represents a promising therapeutic strategy for B-ALL.