Page 162 - 2020_07-Haematologica-web

C.R. Soderquist et al.
75% of the CD4+ cases and in the CD4+/CD8+ and CD4- /CD8- cases. The STAT3 D661Y and S614R mutations are well-characterized hotspot mutations that impart greater hydrophobicity to the SH2 dimerization surface and pro- mote STAT3 nuclear localization and activation.29 These mutations have been described in a myriad of lymphoid neoplasms and are quite frequent in T-large granular lymphocytic leukemia.29 Perry et al. did not detect STAT3 SH2 domain hotspot mutations in five cases analyzed by Sanger sequencing, although all tested cases were CD8+.12 Deletion of SOCS1, a negative regulator of the JAK family proteins,30 which was seen in a colonic CD4+ ITLPD, is a recurrent abnormality in a variety of T-cell lymphomas and more commonly reported in mycosis fungoides.31 We confirm that STAT3-JAK2 rearrangement is a recurrent event in CD4+ ITLPD although this alter- ation was only observed in one (25%) of our cases com- pared to four of five (80%) cases in the series reported by Sharma et al.15
Loss-of-function mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D) represented the next most commonly altered gene class, identified in 40% of cases and restricted to CD4+, CD4+/CD8+, and CD4-/CD8- cases. Mutations in epigenetic modifiers, which are believed to be early events in lymphomagenesis32,33 and known to cooperate with other mutations in fostering neoplastic transformation,33,34 have also been reported in diverse T- cell malignancies.33,35 However, in contrast to other T-cell lymphomas,36 IDH1/2 mutations were not observed in any ITLPD. Although not recurrent, mutations in CDKN2A and TNFAIP3 suggest roles of cell cycle deregulation37 and NF-kB activation38 in the pathogenesis of at least some ITLPD.
Structural chromosome alterations recurrently targeting the 3’ UTR of the IL2 gene, which were identified in 50% of the CD8+ ITLPD, have not been described before. The rearrangements and deletions led to the loss of most or all of the regulatory ARE involved in mRNA stability. Studies in mitogen-stimulated Jurkat cells have shown that dele- tion of these regulatory elements, which act as binding sites for components of the mRNA degradation machin- ery,39 results in a longer half-life of IL2 mRNA.40 Whether these alterations lead to changes in the cellular localization of the IL2 transcript or affect the assembly or composition of protein complexes that modulate activities beyond its 3’ UTR-independent functions has not been investigated. An IL2-TNFRSF17 rearrangement,41 resulting from t(4;16)(q26;p13),41 was previously reported in a CD4+ ITLPD.9 However, in contrast to our cases, the breakpoints in that case mapped to intron 3 of IL2 and exon 1 of the B- cell maturation antigen (BCMA) gene, also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17).41 The authors detected chimeric IL2- TNFRSF17 mRNA, but no fusion protein was identified. The functional significance of the prior and current IL2 genetic alterations remains unknown.
Despite the frequent JAK-STAT pathway gene muta- tions and structural alteration of the IL2 gene, which encodes a key T-cell cytokine that signals via the JAK- STAT pathway,42 none of the ITLPD analyzed showed high-level pSTAT3 or pSTAT5 expression. Our findings are similar to those of Perry et al. who also did not observe significant pSTAT3 expression,12 but contrast with those of Sharma et al. who reported pSTAT5 expression in three of four cases with STAT3-JAK2 rearrangements.15 The rea-
sons for these discrepant findings are unclear. It is plausi- ble that the mutations simply augment the sensitivity of ITLPD to cytokine stimulation, enhancing ligand-mediat- ed signaling as described in other T-cell lymphomas,43 and aberrant proliferations of intraepithelial lymphocytes in refractory celiac disease type 244 that harbor STAT3 muta- tions.
On analysis of serial samples, acquisition of additional mutations, including those targeting genes involved in the DNA damage response (TP53, POLE) were only identified in an ITLPD that transformed to aggressive lymphoma. It is possible that ineffective DNA repair mechanisms fueled acquisition of additional mutations and complex chromo- some changes in this case.11 It is unclear if prolonged aza- thioprine therapy played a role in genomic evolution. Nonetheless, this and other cases in our series as well as those published previously highlight the futility of geno- toxic chemotherapeutic agents for treating ITLPD of the GI tract. The prognostic relevance of periodic genetic analysis needs to be assessed in future larger studies.
Our findings indicate that ITLPD of the GI tract share certain pathogenic mechanisms with other intestinal T- cell lymphomas. As in our cohort, mutations in JAK-STAT pathway genes represent the most frequent alterations in EATL, MEITL, and intestinal T-cell lymphoma, not other- wise specified.17-21 Similarly, loss-of-function mutations in epigenetic modifier genes and DNA damage repair genes have also been reported in aggressive intestinal T-cell lym- phomas.17,18 In contrast to EATL and MEITL, however, SETD2 mutations or deletions were not seen in any ITLPD and the burden of pathogenic alterations in ITLPD appears lower.17,18
ITLPD of the GI tract are immunophenotypically het- erogeneous diseases. Our study revealed a few unique features that are worth highlighting. In addition to CD4+, CD8+, and CD4-/CD8- ITLPD, we describe a CD4+/CD8+ (double-positive) case. Two ITLPD with a similar pheno- type were recently reported from the USA and China.15,45 Two of our CD8+ ITLPD expressed CD103, which has not been documented before. Prior sporadic cases of CD103+ ITLPD have all been of CD4 T-cell lineage.10,13 These ITLPD could arise from αE integrin-expressing lamina propria T cells,46 but the possibility of activation- induced upregulation of CD103 cannot be excluded.47,48 Of note, one CD103+ CD8+ ITLPD also showed focal CD56 expression. Distinguishing such cases from MEITL can be challenging; however, in addition to the clinical presentation and course, the presence of small lympho- cytes with bland cytomorphology confined to the lamina propria, absent MATK expression, and a low Ki-67 index, can help establish a diagnosis of ITLPD. Evaluation of SETD2 and H3K36me3 expression can also aid in differ- entiating ITLPD from MEITL, which frequently show loss of SETD2 and H3K36 trimethylation.17
ITLPD of the GI tract are thought to originate from mucosal T cells, but the cell of origin of different disease subsets has not been clarified. Absence of FoxP3 and T- follicular helper (TFH) cell markers in the current and pre- viously reported CD4+ ITLPD11,16 argues against their der- ivation from regulatory T cells or TFH cells. Based on expression of T-bet and GATA3, which are transcription factors regulating CD4+ Th1 vs. Th2 cell fate decisions, the CD4+ and CD4+/CD8+ ITLPD in our series displayed Th1, Th2, or hybrid Th1/2 profiles. It is not known whether ITLPD with the latter profile develop directly
1904
haematologica | 2020; 105(7)