Cutaneous blastic plasmacytoid dendritic cell neoplasm arising in the context of <i>TET2</i> and <i>ZRSR2</i> mutated clonal cytopenias of unknown significance, secondary to somatic copy number losses involving <i>CDK2NA/2NB</i> and <i>MTAP</i>
Authors: Marissa Li, Mithun Shah, Moritz Binder, Terra Lasho, Ryan Carr, Abhishek Mangaonkar, Naseema Gangat, Giacomo Coltro, Ayalew Tefferi, Linda Dao, Margot Peters, April Chiu, Mrinal M. Patnaik
Journal: American Journal of Hematology (2019)

Blastic plasmacytoid dendritic cell (pDC) neoplasm (BPDCN) is an aggressive myeloid malignancy with cutaneous, lymph node and bone marrow involvement (BM), with neoplastic cells characteristically expressing CD4+, CD56+ and one of the pDC-associated antigens—CD123, TCL-1, CD2AP, or CD303/BDCA2, in the absence of lineage-specific markers.1 Cytogenetic abnormalities are seen in 50-60% of patients, while next generation sequencing NGS) assays have identified recurrent somatic mutations involving TET2, TP53, NPM1, NRAS,FLT3, and IKZF1.2 Somatic copy number abnormalities (SCNA) involving CDKN2A/CDKN2B, CDKN1B and RB1, amongst others have been documented in BPDCN.3 Clonal cytopenias of unknown significance (CCUS) are a recently classified spectrum of premalignant disorders that occur as a consequence of selective somatic clonal proliferation. This is in the context of peripheral blood cytopenias and absence of a pathologically defined hematological malignancy.1 Common gene mutations encountered in CCUS include DNMT3A, TET2 and ASXL1; mutations typically associated with age related clonal hematopoiesis and with myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).2 Approximately 10%-20% of patients with BPDCN have an antecedent history of a myeloid malignancy (MDS/AML or CML),3 but the prevalence rates of antecedent CCUS remain unknown. In addition, we have recently demonstrated relevant genetic events that resulted in the transformation of a patient with chronic myelomonocytic leukemia (CMML) to BPDCN, secondary to biallelic inactivation of the RB1 gene, suggesting common clonal origins for overlapping myeloid malignancies.4 In this report we describe a patient with long standing CCUS that went on to develop cutaneous BPDCN due to SCNA, involving important check point regulators restricted to the skin only. A 68-year-old gentleman with pancytopenia consistent with TET2 and ZRSR2-mutated CCUS first presented to us, after developing violaceous skin lesions on his trunk and face. He had been monitored for his pancytopenia for approximately 4 years, after a BM biopsy revealed no morphologic evidence of dysplasia and a normal karyotype (Figure 1). Samples of a skin lesion and BM biopsy were obtained. Hybrid capture-next generation sequencing (NGS) of BM mononuclear cells demonstrated two TET2 mutations [c.2428delC; p.Q180Rfs*3 (variant allele frequency/VAF-26%), c.3454G > T; p.G1152* (VAF-27%)] and a ZRSR2 mutation [c.312 + 1 G > T (VAF-81%)] (Table S1). The skin biopsy was consistent with involvement by BPDCN, while the bone marrow once again demonstrated no morphological evidence for a myeloid malignancy (Figure 2). Of note, scattered CD123 positive plasmacytoid dendritic cell nodules were seen in the BM (Figure 2). A PET CT scan of the chest, abdomen and pelvis did not demonstrate any additional site of disease. The skin biopsy specimen, along with a peripheral blood control, was then subjected to hybrid capture-NGS. The NGS results on the skin identified the same dual TET2 [p.Q180Rfs*3 (32.9%) and p.G1152* (38.6%)] and a ZRSR2 [c.312 + 1 G > T (75.6%)] mutation with a slight increase in the TET2 VAF. However, in addition, there were SCNA (copy number losses) involving CDKN2A, CDKN2B, and MTAP that were detected in the skin biopsy specimen only. The tumor mutational burden was 0.8 m/MB (16th percentile); germline variants of unclear significance (VUS) were identified in PALB2, AXIN2, and MSH6, while two somatic VUS in IKZF1 (VAF-19.9%) and RANBP2 (7.4%) were also seen (Table S2). The patient was treated with three cycles of tagraxofusp (an anti CD123 antibody-drug conjugate) and demonstrated near complete resolution of the skin lesions before undergoing allogeneic hematopoietic stem cell transplantation. On day +60 post-transplant he remains in complete remission and has not experienced significant complications. The most common initial presentation of BPDCN is violaceous cutaneous lesions, with or without BM involvement.3 Very rarely, do patients present with an acute leukemic state without skin findings. Based on an Italian study in 2012, about 10%-20% of patients who developed BPDCN had an antecedent history of MDS, AML or CML.3 However, this is the first report to detail the evolution of skin limited BPDCN due to clonal evolution arising in the context of expanded clonal hematopoiesis. Somatic copy number alterations in BPDCN have been documented in both the skin and BM, with common abnormalities being SCNA of CDKN2A/CDKN2B, RB1, CDKN1B, LATS, IKZF and MTAP.5, 6 Also, CDKN2A (cyclin dependent kinase) encodes p16 and p14, proteins that serve as critical regulators of cell growth, with p16 inhibiting CDK4 and 6 preventing them from stimulating cell proliferation (G1 phase arrest), and p14 binding to MDM2, stimulating a p53-mediated cell cycle arrest and apoptosis.7 Similarly, CDKN2B encodes p15, a protein that also regulates cell cycle through the inhibition of CDK4 and 6, resulting in a G1 phase arrest.8 On the other hand, MTAP (5′-methylthioadenosine phosphorylase), commonly co-deleted with CDKN2A/B due to chromosomal proximity, participates in the methionine salvage pathway that metabolizes methylthioadenosine (MTA) to adenine and methionine, and has been shown to have an independent effect in cell migration and invasion.9 In addition, the recent US FDA approval of Tagraxofusp, a CD123-directed cytotoxin consisting of recombinant human interleukin-3 fused to a truncated diphtheria toxin has revolutionized the management of BPDCN, with overall response rates of 90% in previously untreated patients10; substantially improving outcomes. However, this drug is not curative, and especially for transplant ineligible patients, there is a strong need for additional, more definitive rationally derived therapies. In this regard, it has been shown that in CDKN2A/MTAP-deleted tumors, MTA accumulation creates a hypomorphic PRMT5 (Protein arginine N-methyltransferase 5) state that is selectively sensitized toward further PRMT5 inhibition.9 It remains intriguing if in these patients, early intervention with PRMT5 inhibitors might abrogate clonal progression. In summary, with the help of this illustrative case we demonstrate the common clonal origins of cutaneous BPDCN, arising from a pre-existing CCUS. By demonstrating SCNA in CDKN2A/B and MTAP in the skin only, and the coexistence of TET2 and ZRSR2 mutations in the skin and the BM, we infer that SCNA involving critical cell cycle regulators and the purine nucleotide pathway, could allow for the development of a morphologically distinct entity such as BPDCN. Our ability to monitor and understand clonal evolution using “multi-omic” technologies interrogating the genome, transcriptome (RNA-seq), epigenome (chromatin and methylome), including enhancer elements (ATAC-seq) and single cell sequencing methods, will likely shed more light on the specific sequence of events involved in the evolution of CCUS to BPDCN and for that matter other myeloid malignancies. Whether this would allow for the development of newer therapeutic strategies that might abrogate clonal progression remains to be seen. Informed consent from the patient was obtained to share relevant data as outlined in the manuscript, including genetic information. Current publication is supported in part by grants from the “The Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA”. TABLE S1 TABLE S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.