Contributions
Abstract: PB1689
Type: Publication Only
Background
We have reported that ADAM28 promoted the invasion and survival of leukemic cells; however, the precise prognostic relevance between ADAM28 and acute myeloid leukemia (AML) remain unknown.
Aims
To compare the outcome of AML depending on the expression of ADAM28.
Methods
A well-established NOD/SCID xenotransplantation model was used to test the effect of ADAM28 on the AML burden. Bone marrow samples were obtained from adults with AML (N=107) and normal individuals (N=24) recruited at the Hematology Department of Peking University People’s Hospital between May 2013 and May 2014, among which 32 were part of the test group and 75 were prospectively enrolled to the validation group.
Results
The relative expression level of ADAM28 in the leukemic cells of the testing group was significantly higher than that in the control BM cells (0.98± 0.09 vs 0.49 ± 0.04; p < 0.001). Furthermore, the ADAM28 level in the CSF of patients with CNSL was significantly higher than that without CNSL (2.87±0.81 vs 0.50±0.08, p<0.0001). In the intrafemoral xenotransplantation experiments, peripheral leukocyte counts were significantly lower in mice receiving ADAM28-knock out (KO) cells compared with those in mice with control cells. A Kaplan-Meier plot demonstrates that mice bearing ADAM28-KO cells survived longer compared with control mice (P= 0.017). Slighter splenomegaly was observed in mice with ADAM28-KO cells. Additionally, knock out of ADAM28 decreases the incidence of CNS infiltration. In the in vitro experiment, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. To validate the effect of ADAM28 protein level on the prognosis of AML patients, we extended ADAM28 expression level detection to a validation group of 75 patients with AML. The ADAM28 expression level of the validation group in the bone marrow and CSF between patients with or without CR had the same trend as the testing group. Prognostic analysis revealed that in the enrolled 87 patients (patients with APL were excluded), the CIR and EFS was significantly higher in the ADAM28 high expression group (p=0.003, 0.021 and 0.017 respectively). However, the prognostic analysis in patients with M3 did not differ significantly. Notably, when separately analyzing the impact of the ADAM28 expression level on prognosis within clinically defined risk groups, patients with high ADAM28 expression levels had a significantly higher CIR and worse EFS in the favorable-risk group, and a significantly higher CIR in the intermediate-risk group, but this discrimination was not observed in the poor-risk group. Additionally, patients with high ADAM28 expression presented a significantly higher CIR than the low expression patients in the chemotherapy subgroup, whereas relapse did not differ significantly with the ADAM28 expression level in patients receiving transplantation.
Interestingly, when the median or arithmetic average was taken as the cut-off value of ADAM28 expression, the result of the survival analyses had a similar trend in the favorable-risk group, which might indicate that ADAM28 was a valuable prognostic marker.
Conclusion
In summary, these data provide the first demonstration that high expression of ADAM28 correlates with a high risk of relapse in favorable risk AML patients. This correlation is seen in subjects receiving chemotherapy only but not in those also receiving an HSCT. However, whether these patients would benefit more from HSCT need further validation by prospective large-scale randomized clinical trials.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, Relapse
Abstract: PB1689
Type: Publication Only
Background
We have reported that ADAM28 promoted the invasion and survival of leukemic cells; however, the precise prognostic relevance between ADAM28 and acute myeloid leukemia (AML) remain unknown.
Aims
To compare the outcome of AML depending on the expression of ADAM28.
Methods
A well-established NOD/SCID xenotransplantation model was used to test the effect of ADAM28 on the AML burden. Bone marrow samples were obtained from adults with AML (N=107) and normal individuals (N=24) recruited at the Hematology Department of Peking University People’s Hospital between May 2013 and May 2014, among which 32 were part of the test group and 75 were prospectively enrolled to the validation group.
Results
The relative expression level of ADAM28 in the leukemic cells of the testing group was significantly higher than that in the control BM cells (0.98± 0.09 vs 0.49 ± 0.04; p < 0.001). Furthermore, the ADAM28 level in the CSF of patients with CNSL was significantly higher than that without CNSL (2.87±0.81 vs 0.50±0.08, p<0.0001). In the intrafemoral xenotransplantation experiments, peripheral leukocyte counts were significantly lower in mice receiving ADAM28-knock out (KO) cells compared with those in mice with control cells. A Kaplan-Meier plot demonstrates that mice bearing ADAM28-KO cells survived longer compared with control mice (P= 0.017). Slighter splenomegaly was observed in mice with ADAM28-KO cells. Additionally, knock out of ADAM28 decreases the incidence of CNS infiltration. In the in vitro experiment, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. To validate the effect of ADAM28 protein level on the prognosis of AML patients, we extended ADAM28 expression level detection to a validation group of 75 patients with AML. The ADAM28 expression level of the validation group in the bone marrow and CSF between patients with or without CR had the same trend as the testing group. Prognostic analysis revealed that in the enrolled 87 patients (patients with APL were excluded), the CIR and EFS was significantly higher in the ADAM28 high expression group (p=0.003, 0.021 and 0.017 respectively). However, the prognostic analysis in patients with M3 did not differ significantly. Notably, when separately analyzing the impact of the ADAM28 expression level on prognosis within clinically defined risk groups, patients with high ADAM28 expression levels had a significantly higher CIR and worse EFS in the favorable-risk group, and a significantly higher CIR in the intermediate-risk group, but this discrimination was not observed in the poor-risk group. Additionally, patients with high ADAM28 expression presented a significantly higher CIR than the low expression patients in the chemotherapy subgroup, whereas relapse did not differ significantly with the ADAM28 expression level in patients receiving transplantation.
Interestingly, when the median or arithmetic average was taken as the cut-off value of ADAM28 expression, the result of the survival analyses had a similar trend in the favorable-risk group, which might indicate that ADAM28 was a valuable prognostic marker.
Conclusion
In summary, these data provide the first demonstration that high expression of ADAM28 correlates with a high risk of relapse in favorable risk AML patients. This correlation is seen in subjects receiving chemotherapy only but not in those also receiving an HSCT. However, whether these patients would benefit more from HSCT need further validation by prospective large-scale randomized clinical trials.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, Relapse