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Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation

Baohong Wu1, Xiangyu Pan1, Xuelan Chen1

  • 1Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan China.

Signal Transduction and Targeted Therapy
|May 3, 2019
PubMed

Insights

UTX (KDM6A) mutations drive MDS and AML by blocking cell differentiation. Inhibiting LSD1 with SP2509 specifically promotes differentiation in UTX-deficient cells, offering a new therapeutic strategy for these leukemias.

Area of Science:

  • Epigenetics
  • Hematopoiesis
  • Cancer Biology

Background:

  • UTX (KDM6A) is a frequently mutated epigenetic regulator in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
  • UTX mutations are implicated in blocking hematopoietic stem and progenitor cell (HSPC) differentiation, contributing to MDS and AML development.
  • Targeting the differentiation block in HSPCs presents a potential therapeutic avenue for these hematologic malignancies.

Purpose of the Study:

  • To identify small molecules that can overcome the differentiation block in HSPCs caused by UTX deficiency.
  • To investigate the therapeutic potential of identified compounds in UTX-deficient MDS and AML models.
  • To elucidate the molecular mechanisms by which UTX regulates HSPC differentiation and leukemogenesis.

Main Methods:

  • Epigenetic drug library screening to identify compounds promoting differentiation in UTX-deficient HSPCs.
  • Transcriptome profiling to analyze gene expression changes in response to UTX deficiency and drug treatment.
  • Assessment of histone methylation levels (H3K4) in UTX-deficient and treated cells.
  • In vitro and in vivo studies using UTX-deficient AML cell lines and mouse models to evaluate SP2509 efficacy.

Main Results:

  • SP2509, a selective LSD1 inhibitor, specifically promoted differentiation of UTX-null HSPCs while sparing wild-type HSPCs.
  • UTX loss reduced expression of differentiation and tumor suppressor genes; SP2509 treatment reversed these changes.
  • UTX deficiency decreased H3K4 methylation, which was partially restored by SP2509 treatment.
  • SP2509 promoted differentiation of UTX-null AML cells in vitro and in vivo, extending survival in leukemic mice.

Conclusions:

  • SP2509 represents a novel therapeutic strategy for differentiation therapy in UTX-deficient MDS and AML.
  • Targeting LSD1 can specifically overcome the differentiation block in premalignant and malignant cells with UTX deficiency.
  • This study provides insights into UTX's role in regulating HSPC function and its implications in leukemogenesis.
Keywords:
Cancer

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