SOHO 2019 | XPO7 as a novel therapeutic target for TP53-AML

During the 7^th Society of Hematologic Oncology (SOHO) annual meeting, in Houston, TX, US, a session on acute myeloid leukemia (AML) was held. Yuichiro Semba, Kyushu University Graduate School of Medical Sciences, Fukuoka, JP, presented a talk entitled “CRISPR-Cas9 Screen Identifies XPO7 as a Novel Therapeutic Target for TP53-Mutated AML”.¹

AML is a heterogeneous disease characterized by various genetic aberrations, some of which can be prognostic. It has already been established that patients with complex karyotype have poor outcomes.² Mutations in TP53 are commonly associated with a complex karyotype, with an incidence of 69-78%, are a strong AML risk-factor.^1,2 In this pre-clinical genomic study, the investigators sought to identify specific gene targets and pathways that are critical for the survival of TP53-mutated AML cells with the hope of findings novel drug targets. For this, they performed a genome-wide CRISPR-Cas9 screen in AML cell lines in vitro.

AML cell lines

• All cell lines were established from mice models that were transplanted with bone marrow stem cells harboring the MLL/AF9 leukemia oncogene (AML mice)
• Leukemic cells were harvested from the AML mice and were established as cell lines with a normal wild-type Trp53 (the mouse homolog of TP53) and normal karyotype
• Trp53-mutated AML cell lines were established by single-guide RNA targeting of Trp53 in the wild-type lines

Genome-wide CRISPR-Cas9 screen 

• A CRISPR-Cas9 library screen was used to identify Trp53-dependent genes whose loss was lethal in Trp53-mutated cells but not in wildtype Trp53 AML cells
• The authors identified XPO7, a nuclear transport receptor gene expressed in leukemias as one of the genes that were dependent on Trp53
• To further validate this the authors compared the proliferation rate and cell cycle transition of wild-type or Trp53-knockout AML cell lines following XPO7 downregulation in vitro
  • Loss of XPO7 led to a significant decrease in proliferation and cell cycle transition only in the TrpP53-knockout AML cell lines and not the wild-type ones
• By Western blotting and qPCR, the investigators uncovered that XPO7 retains Trp53 in the nucleus of the Trp53-mutated AML cells
  • This mechanism shows that XPO7 acts as a TP53-dependent tumor suppressor in wild-type AML cells
• This result was further verified in human TP53-mutated AML cell lines in vitro, with XPO7 knockout being toxic and delaying cell cycle progression

Conclusions 

The investigators identified a synthetic lethal association between expression of XPO7 and TP53 with XPO7 loss leading to the suppression of TP53-mutated AML cell proliferation. Based on these results and the fact that XPO7 mRNA is significantly upregulated in AML patients (The Cancer Genome Atlas database)³ it is likely that the nuclear transport protein XPO7 may serve as a novel therapeutic target for TP53-mutated AML.