Page 14 - Haematologica - Vol. 105 n. 6 - June 2020

Editorials
Mutations in Myelodysplastic Syndromes. N Engl J Med.
2011;364(26):2496-2506.
3. Hunter AM, Sallman DA. Current status and new treatment
approaches in TP53 mutated AML. Best Pract Res Clin Haematol.
2019;32(2):134-144.
4. Sallman DA, Komrokji R, Vaupel C, et al. Impact of TP53 mutation
variant allele frequency on phenotype and outcomes in myelodys-
plastic syndromes. Leukemia. 2016;30(3):666-673.
5. Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status
divides myelodysplastic syndromes with complex karyotypes into
distinct prognostic subgroups. Leukemia. 2019;33(7):1747-1758.
6. Montalban-Bravo G, Kanagal-Shamanna R, Benton CB, et al. Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes. Blood Adv.
2020;4(3):482-495.
7. Bernard E, Nannya Y, Yoshizato T, et al. TP53 State Dictates
Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes. Blood. 2019;134(Supplement_1):675- 675.
8. Hunter AM, Sallman DA. Targeting TP53 Mutations in Myelodysplastic Syndromes. Hematol Oncol Clin North Am. 2020;34(2):421-440.
9. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):676-676.
10. Cluzeau T, Sebert M, Rahmé R, et al. APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM). Blood. 2019;134(Supplement_1):677-677.
11. Maslah N, Salomao N, Drevon L, et al. Synergistic effects of PRIMA- 1Met (APR-246) and Azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2019;xxx
12. Boettcher S, Miller PG, Sharma R, et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignan- cies. Science. 2019;365(6453):599-604.
13. Lambert JM, Gorzov P, Veprintsev DB, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15(5):376-388.
14. Zhang Q, Bykov VJN, Wiman KG, Zawacka-Pankau J. APR-246 reac- tivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9(5):439.
15. Lehmann S, Bykov VJ, Ali D, et al. Targeting p53 in vivo: a first-in- human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30(29):3633-3639.
16. Deneberg S, Cherif H, Lazarevic V, et al. An open-label phase I dose- finding study of APR-246 in hematological malignancies. Blood Cancer J. 2016;6(7):e447.
17. Cluzeau T, Dubois A, Jacquel A, et al. Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines. Oncotarget. 2014;5(12):4384-4391.
18. Bykov VJ, Zhang Q, Zhang M, Ceder S, Abrahmsen L, Wiman KG. Targeting of Mutant p53 and the Cellular Redox Balance by APR-246 as a Strategy for Efficient Cancer Therapy. Front Oncol. 2016;6:21.
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20. Demir S, Boldrin E, Sun Q, et al. Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(1):170-181.
Peripheral T-cell lymphoma diagnosis: building a molecular tool
Miguel A Piris1,2
1Department of Pathology, Hospital Universitario, Fundación Jiménez Díaz and 2CIBERONC, Madrid, Spain E-mail: MIGUEL A PIRIS - mapirispinilla@gmail.com
doi:10.3324/haematol.2020.249052
T-cell lymphoma (TCL) has quite a poor probability of survival (around 25-30% of patients after 5 years), which contrasts with the progress that has recently been made in Hodgkin lymphoma and B-cell lymphoma.1-3 Some recently defined TCL types, such as anaplastic large-cell lymphoma (ALCL), have a better clinical outcome. However, the majority of cases diag- nosed with peripheral T-cell lymphoma (PTCL) will even- tually die of the disease, and in some specific tumor types, such as intestinal TCL, the prognosis is even more miserable.
Poor survival probability in this context is associated with serious difficulties in lymphoma diagnosis when using routine morphological and immunohistochemistry tools. PTCL classification involves division into multiple subtypes, typically of low frequency and with hazy dis- tinctions (Figure 1). As a consequence, different studies coincide in achieving a very low rate of reproducibility in TCL diagnosis, especially in recognizing ALK-negative ALCL, and distinguishing between PTCL-not otherwise specified (NOS) and PTCL with TFH phenotype or angioimmunoblastic TCL.4
An important feature of this situation is that the relative frequencies of the tumor types are quite low, which makes it difficult to design and develop clinical trials, and this hampers the introduction of new drugs for PTCL ther- apy.
Nevertheless, these difficulties have inspired some research groups to provide essential information about the molecular basis of TCL pathogenesis, and to identify some attractive and challenging therapeutic targets.5-9
Drieux and co-workers,10 in a joint project involving French, Belgian and Swiss hospitals, are now addressing the radical proposal that molecular diagnosis may give a more precise and reproducible way of classifying TCL cases. Using a technique applicable to paraffin-embedded tissue, they measure the expression of 20 genes, including 17 markers relevant to T-cell classification, one Epstein- Barr virus-related transcript, and frequently mutated vari- ants of RHOA (G17V) and IDH2 (R172K/T). Selected genes allow the identification of several entities: TFH cells, the normal counterparts of angioimmunoblastic TCL; TH1 and TH2 phenotypes, which reflect the diver- sity of PTCL-NOS; T-regulatory cells, for distinguishing ATLL; the cytoxic markers, CD30 and ALK, for identifying ALCL; and CD56 and EBER1, to discriminate T/natural killer (NK)-cell lymphomas.
The results validate the solid basis of the currently used PTCL classification scheme, and highlight the similarity between angioimmunoblastic TCL and PTCL-TFH. The findings show a group of cases with simultaneous expres- sion of TFH markers and TH2 (GATA3), and indicate that ALK-negative ALCL is a heterogeneous condition. Cases of PTCL-NOS appear to be extremely heterogeneous,
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