Loss of function of Cdh1 causes cell fragility due to aberrant G2/M checkpoint and develops resistant disease in acute lymphoblastic leukemia in mouse and human

Cdh1 regulates not only mitotic phase and G1 phase, but also G2 checkpoint under irradiation-induced DNA damage. Despite several reports indicating its potential as tumor suppressor, how Cdh1 affects tumorigenesis or tumor progression and its clinical implementation has yet to be evaluated. Considering the pivotal role of Cdh1 on DNA repair, we hypothesized that Cdh1 loss also causes fragility of tumor cells to DNA damage under oncogenic stress or chemotherapy. To test this hypothesis, we established a Cdh1 gene-trapped B cell acute lymphoblastic leukemia (B-ALL) mouse model. Cdh1-deficient B-ALL mice survived longer than Cdh1-intact group, with higher susceptibility to DNA damage. Consistently, reverse phase protein array-based analysis of more than 200 human adult B-ALL samples showed that low Cdh1 was associated with high complete remission rates and long remission durations. Furthermore, the clinical benefit with lower Cdh1 expression diminished after relapse, supported by mouse experiments showing that secondary/tertiary transplants of Cdh1-deficient B-ALL cells developed more progressive/resistant disease than Cdh1-intact group. This indicated that prolonged inactivation of Cdh1 eventually develops resistant clones. Our results collectively demonstrated that Cdh1 is a potential predictive biomarker of B-ALL chemosensitivity, but also alerting that synthetic lethality by targeting DNA repair system may eventually induce resistant disease due to genetic instability. Cdh1GT [f-cDNA]/GT [f-cDNA] mice (Cdh1f/f mice), Mx1-Cre transgenic mice were used. N-myc cDNA was cloned into the retroviral vector pMXs-IG. Mx1-Cre expression was induced by intraperitoneally injecting 7- to 8-week-old conditional gene-trap mice (Mx1-Cre(-)/Cdh1f/f, or Mx1-Cre(+)/Cdh1f/f mice) with pIpC. Both genetic groups of mice were selected from the same littermates in each experiment. At 4 weeks after the final pIpC injection, bone marrow mononuclear cells (BM-MNCs) were collected 2days after intraperitoneal injection of 150 mg/kg 5-fluorouracil (5-FU). To investigate the difference in gene signature between Cdh1-intact and -deficient B-ALL cells, we performed gene expression profiling of GFP+ cells in both groups (n = 3 for each). Statistical analysis of differently expressed genes was performed using the Linear Models for Microarray Data (limma) package in R/Bioconductor.