Page 137 - 2019_05-HaematologicaMondo-web

CD147 as potential therapeutic target in AML
inhibit the viability of AML cells and synergize with cytarabine in inhibiting AML cell viability.46 Importantly, we also showed that AC-73 increases ATO-induced autophagy in both M3 and non-M3 leukemic cells, indi- cating a possible synergistic anti-tumor interaction of ATO with an inhibitor of CD147, both agents being able to induce autophagy.
The analysis of CD147 expression in AML subsets pre- sented several interesting findings. First, CD147 is over- expressed in all French-American-British classification AML subtypes, and particularly in AML-M3; a finding confirmed through the analysis of primary AML samples. This finding was also corroborated by the analysis of the TCGA data set. Moreover, about 20% of non-M3 AMLs displayed elevated CD147 levels. Although the overall long-term survival of these patients (defined as highly- expressing CD147) was similar to the other two non-M3 AML groups (defined as middle- and low-expressing
CD147), death occurs earlier in patients showing high expression of CD147. This observation supports the neg- ative prognostic role of high CD147 expression levels in AMLs, as observed also in other tumors, including some hematologic neoplasia.3,19 Other recurrent AML mutations,1,2 such as NPM1, FLT3-ITD and DNMT3A, were not associated to particularly elevated levels of CD147. Therefore, AC-73 used in combination with Ara- C or ATO may have clinical potential implications in treat- ment of AML patients expressing CD147. Future toxico- logical and pharmacodynamic studies in suitable animal models will be required for a preclinical evaluation of the possible impact of AC-73 as an anti-leukemic drug.
Our study also reports for the first time that CD147 is expressed in a sub-fraction CD34+CD371+ of AML cells that is able to engraft immunodeficient mice,20 CD34 being predominantly regarded as a marker of hematopoi- etic stem cells (HSC) and HPCs, and CD371 as a marker of
AB
Figure 7. CD147 gene expression level does not predict overall sur- vival in acute myeloid leukemia (AML), but is correlated in early death of (non-M3)-AML patients. (A) Relationship between the most
CD
levels in 3 groups: (CD147<70); medium (CD147, range, 70-120); high (CD147 >120). (D) Kaplan-Meier survival analysis in the new group of (non- M3)-AML patients deceased with- in 50-60 months years after diag- nosis, indicates that the kinetics of death is more rapid (within 20 months) among CD147 high patients, as compared with those with low (P<0.01) or medium (P<0.001) CD147 levels; P-values calculated by log-rank test. The histograms show that white blood count (WBC) number, age at diag- nosis and proportion of patients with poor cytogenetics were com- parable in the 3 (non-M3)-AML subgroups subdivided according to CD147 expression level.
recurrent gene
observed in all AMLs and the level of CD147 mRNA expression, according to the TCGA dataset. (B) CD147 mRNA levels were ana- lyzed in AMLs stratified into 3 risk groups: poor, intermediate and favorable, according to the European LeukemiaNet (ENL) risk classification. (C) Kaplan-Meier survival analysis in a new group of AML patients that excludes AML- M3 patients, based on CD147 gene expression and stratified according to their CD147 mRNA
mutations
low
High vs. medium P=0.0003 High vs. low P=0.003
haematologica | 2019; 104(5)
983