Targeting protein tyrosine phosphatase non-receptor type 6 (PTPN6) as a therapeutic strategy in acute myeloid leukemia

Cell Biol Toxicol. 2024 Dec 21;41(1):11. doi: 10.1007/s10565-024-09965-3.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid progenitor cells. Despite advancements in treatment, the prognosis for AML patients remains poor, highlighting the need for novel therapeutic targets. Protein Tyrosine Phosphatase Non-Receptor Type 6 (PTPN6), also known as SHP-1, is a critical regulator of hematopoietic cell signaling and has been implicated in various leukemias. This study investigates the therapeutic potential of targeting PTPN6 in AML. We employed both in vitro and in vivo models to evaluate the effects of PTPN6 inhibition on AML cell proliferation, apoptosis, and differentiation. Our results demonstrate that PTPN6 inhibition leads to a significant reduction in AML cell viability, induces apoptosis, and promotes differentiation of leukemic cells into mature myeloid cells. Mechanistic studies revealed that PTPN6 inhibition disrupts key signaling pathways involved in AML pathogenesis, including the JAK/STAT and PI3K/AKT pathways. Furthermore, the combination of PTPN6 inhibitors with standard chemotherapeutic agents exhibited a synergistic effect, enhancing the overall therapeutic efficacy. These findings suggest that PTPN6 is a promising therapeutic target in AML and warrants further investigation into the development of PTPN6 inhibitors for clinical application in AML treatment.

Keywords: Acute myeloid leukemia; Ferroptosis-related genes; HMOX1-TLR4 axis; PTPN6.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis* / drug effects
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Cell Survival / drug effects
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6* / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction* / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • PTPN6 protein, human
  • Antineoplastic Agents
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt