Page 169 - Haematologica April 2020

CD99 overexpression in AML
integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway;37 they also found that ERK is essential for CD99 homotypic aggregation.46 CD99 homotypic interactions driving a negative feedback loop or via its sub- sequent binding with caveolin may explain the later inhi- bition of ERK and SRC.42 CD99 was found to drive termi- nal differentiation of osteosarcoma cells via activation of membrane-bound/cytoplasmic ERK rather than affecting its nuclear localization.47 Yet, in EWS, CD99 knockdown led to prolonged nuclear phosphorylation of ERK1/2 and neural differentiation.48 In addition, CD99mAb was shown to act as an agonist, and reported similar pheno- types to those observed in our study.46,49 Both CD99-L ectopic expression and CD99mAb induced similar cellular effects, and, likewise, modulated P-SRC. However, further biochemical studies are required to establish whether CD99mAb acts as an agonist for CD99 long isoform.
In summary, our results present unique insights into the
clinical, functional, and mechanistic roles of CD99 iso- forms in AML. The mechanisms by which CD99 is up- regulated and those that govern its function in leukemia initiation remain to be investigated.
Acknowledgments
We would like to thank the Bioinformatics core at the Norris Medical Library, University of Southern California and TCGA. This work was supported by grant UL1TR001855 from the National Center for Advancing Translational Science (NCATS) of the US National Institutes of Health, the Southern California Clinical, Translational Science Institute KL-2 funding (KL2TR001854) and the Ming Hsieh Institute Funding. AMNB is funded by the BMBF grant 01ZZ1804B (DIFUTURE). KM is supported by the German Research Foundation (DFG SFB 1243). TH is supported by the Wilhelm Sander Foundation (2013.086.2) and by the Physician Scientists Grant (G- 509200-004) from the Helmholtz Zentrum München.
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