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CD30+ primary cutaneous LPD
hallmark of cancer and a potential target for therapy.70 DNA methylation profiling studies have not been done specifically in cutaneous ALCL; data derived from the analysis of systemic ALCL show an ALK-independent methylation signature, characteristic of and different from that of other peripheral T-cell lymphomas, establishing a relation with the promoter DNA methylation of early T- cell stages.71
The enhancer of the zeste homolog 2 (EZH2) consti- tutes the core catalytic subunit of polycomb repressive complex2 (PRC2) and has a “canonical” function as a PRC2-dependent lysine 27 of the histone H3 (H3K27) methylator, which can also methylate a number of non- histone proteins, thereby promoting transcriptional acti- vation, and making it a potential therapeutic target.72 Yi et al. found EZH2 overexpression in pcALCL and large cell transformed cutaneous T-cell lymphomas, in which it reg- ulates apoptosis, cell-cycling in the neoplastic cells, and the interaction between the tumor and its microenviron- ment.73
Non-coding RNA play an important epigenetic regulato- ry role that has implications for cell development and can- cer, above all in the pathogenesis of T-cell lymphomas.74 MicroRNA (miRNA, miR) are small, non-coding RNA molecules that regulate gene expression at the post-tran- scriptional level by targeting the 3’-untranslated regions of messenger RNA to promote their degradation or decrease their translation.75 Several studies have identified different miRNA signatures for CD30+ pcALCL.62,76-78 Benner et al. showed upregulation of an oncogenic miRNA signature in pcALCL comprising miR-155, miR-27b, miR-30c and miR- 29.77 Sandoval’s study confirmed the upregulation of miR155 and identified upregulation of miR-21, miR-142- 3p/5p, let-7i, miR-424, miR-431, miR-542-5p, miR-29b-1, miR-342-p, and miR-484, with downregulation of some interesting tumor-suppressor miRNA such as miR- 23b/miR-27b, miR-203, miR-205 and miR-125b.78 This miRNA profile reported for pcALCL differs considerably from those reported in systemic ALCL, which suggests a different underlying pathogenic mechanism or reflects dif- ferences in the microenvironment.79,80
In this setting, epigenetic therapy (histone deacetylase inhibitors, such as romidepsin or belinostat, and methyla- tion inhibitors) has shown some benefit in the treatment of ALCL and cutaneous T-cell lymphomas.81,82 In the future, more precise identification of miRNA profiling in pcALCL could allow us to develop specific diagnostic and progression markers and may lead to the use of more spe- cific targeted therapies.
NOTCH signaling in primary cutaneous anaplastic large cell lymphoma
The deregulation of Notch signaling in hematopoietic cells has been linked to the development of several hema- tologic malignancies, including acute lymphoblastic T-cell leukemia, B-cell chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, Hodgkin lymphoma and systemic ALCL.83-88 Increased expression of Notch sig- naling molecules has been described in primary cutaneous CD30+ lymphoproliferative disorders, as previously men- tioned.26 The same group found that pcALCL cells increased their expression of the intracellular domains of Notch receptors Notch1, Notch2, Notch3 and Notch4, as well as of the Notch ligand Delta and the product HES1.89 In addition, it was demonstrated that the inhibition of the
Notch pathway through inhibition of gamma-secretase with gamma-secretase inhibitors induces apoptosis and decreases cell viability in pcALCL cell lines, findings that identify the Notch pathway as a potential therapeutic tar- get in pcALCL.89
CDKN2A-CDKN2B losses in primary cutaneous anaplastic large cell lymphoma
The CDKN2A-CDKN2B locus on the 9p21 chromoso- mal band encodes the proteins p14ARF, p16INK4A and p15INK4B. p14ARF-mdm2-p53 and p16INK4A/ p15INK4B-Rb1 pathways are important for controlling the cell cycle, especially progression between G1 and S phas- es.90 Combined CDKN2A-CDKN2B deletion has been linked to aggressive behavior in cutaneous T-cell lym- phomas,91-95 but more rarely in pcALCL, as confirmed by two research groups.95,96
Other cytogenetic abnormalities in primary cutaneous anaplastic large cell lymphoma
Additional chromosomal alterations, such as gains of 7q31 and losses on 6q16-6q21, 6q27 and 13q34 regions, are recurrently present in pcALCL.31,62,97 Interestingly, these alterations in pcALCL occur mainly in telomeric and cen- tromeric regions. Genomic imbalances have been found in chromosomal regions coding for FGFR1 (8p11), NRAS (1p13.2), MYCN (2p24.1), RAF1 (3p25) and others.98
Targeted therapies for primary cutaneous CD30-positive lymphoproliferative disorders
Currently, complete surgical excision and local radio- therapy are the recommended first-line therapies for soli- tary or grouped localized pcALCL lesions.99 However, the most appropriate treatment in the relapsed/refractory set- ting has not been clearly identified. Multiagent chemotherapy is customarily indicated for extracutaneous tumor spread beyond locoregional lymph nodes. In recent years, brentuximab vedotin, an anti-CD30 antibody-drug conjugate has been proposed as one of the best options for achieving complete remission with low toxicity in these patients.100 ALCANZA, an international, open-label, ran- domized, phase 3, multicenter clinical trial, has shown sig- nificant improvement in objective responses lasting at least 4 months with brentuximab vedotin compared with the physician’s choice of methotrexate or bexarotene in CD30+ cutaneous T-cell lymphomas, especially MF and pcALCL (having excluded Sézary syndrome and LyP from the study, since these are entities in which brentuximab vedotin is successful).101 The mean duration of response to this drug in pcALCL is 7.6 months. Peripheral neuropathy and fatigue are the most commonly reported adverse events (in 57.2% and 35.6% of cases, respectively).102 Recently the US Food and Drug Administration and the European Medicines Agency approved the use of brentux- imab vedotin in cutaneous T-cell lymphomas.
Besides the use of anti-CD30 molecules in the treatment of primary cutaneous CD30+ lymphoproliferative disor- ders, molecular data generated in the study of pcALCL offer multiple opportunities for targeted therapies (Figure 4).
The recognition of convergent mutations and kinase fusions leading to STAT3 activation in a subgroup of pcALCL could allow the use of JAK1/2/3 inhibitors in the
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