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Letters to the Editor
inhibitors was suggested as a valuable strategy to reduce relapse rates in ALCL.14
In the presence of lower NPM-ALK levels, we hypoth- esized that miR-939 overexpression could contribute to fine-tuning the JUNB-mediated oncogenic signaling, fur- ther explaining the favorable outcome of ALK-low ALCL cases. To assess if miR-939 was able to modulate PDGFRB expression through JUNB modulation, we eval- uated PDGFRB expression in Karpas299 and SUP-M2 cells after transfection with miR-939 mimic or negative control. PDGFRB was reduced in both the cell lines after 48 hours of transfection with miR-939 mimic (Figure 3A and Online Supplementary Figure S3). Even though JUN is also necessary to regulate PDGFRB transcription in ALCL,14 our results suggest that miR-939 modulates PDGFRB expression by specifically targeting JUNB, since JUN protein was not affected by miR-939 overexpression (Figure 2D). While JUNB mRNA did not show any signif- icant difference between ALK-high and ALK-low groups (Online Supplementary Figure S4), PDGFRB transcript lev- els were significantly reduced in miR-939_high compared to miR-939_low ALCL cases (Figure 3B). By performing reverse phase protein arrays on ten ALCL tumor tissue samples, PDGFRB protein was also found to be signifi- cantly downregulated in miR-939_high cases (Figure 3C), suggesting that miR-939 could act as an oncosuppressor by reducing PDGFRB expression.
In conclusion, we previously showed that tumors with high or low NPM-ALK levels are characterized by a dif- ferent gene expression profile and a different aggressive- ness. In particular, when expressed at lower levels, ALK is unable to render the transformed lymphocytes com- pletely unresponsive to pathways normally expressed in T cells, such as those involved in interleukin signaling.6 Here we demonstrated that miR-939 expression could contribute to PDGFRB inhibition, a crucial driver for ALCL lymphomagenesis, via JUNB downregulation (Figure 3D). Further investigations will clarify if miR-939 expression could affect anti-CD30 therapies or imatinib treatment efficacy in ALK-low ALCL patients.
Anna Garbin,1,2 Federica Lovisa,1,2 Antony B. Holmes,3 Carlotta C. Damanti,1,2 Ilaria Gallingani,1,2 Elisa Carraro,1 Benedetta Accordi,1,2 Giulia Veltri,1,2 Marco Pizzi,4
Emanuele S.G. d’Amore,5 Marta Pillon,1 Alessandra Biffi,1,2,6 Katia Basso,3,7 and Lara Mussolin1,2
1Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Women and Child Health, University of Padua, Padua, Italy; 2Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy; 3Institute for Cancer Genetics, Columbia University, New York, NY, USA; 4Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padova, Padova, Italy; 5Department of Pathological Anatomy, San Bortolo Hospital, Vicenza, Italy; 6Gene Therapy Program, Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA and 7Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
Correspondence:
LARA MUSSOLIN - lara.mussolin@unipd.it
doi:10.3324/haematol.2019.241307
Disclosures: no conflicts of interests to disclose.
Contributions: AG performed the experiments, analyzed results, prepared figures and wrote the manuscript; FL analyzed results and wrote the manuscript; ABH performed microarray analyses and revised
the manuscript; CCD and IG processed clinical samples and per- formed qRT-PCR analyses; EC and MP collected clinical data, per- formed statistical analyses and revised the manuscript; BA and GV performed Reverse Phase Protein Array experiments and commented on the manuscript; MP and ESGdA performed hemato-pathological revision and commented on the manuscript; AB revised the manuscript; KB supervised microarray analyses and revised the manuscript;
LM conceived and designed research, supervised experimental work and revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding: this work was supported by Fondazione Città della Speranza, Padova, Italy; Fondazione CA.RI.PA.RO, Padova, Italy (grant 17/03 to LM); Camera di Commercio Venezia, Venezia, Italy; Fondazione Roche, Roma, Italy (grant to FL) and Fondazione Umberto Veronesi, Milano, Italy (fellowship to FL); Associazione Italiana contro le Leucemie, sezione provinciale di Treviso (grant to BA).
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