Bone marrow clonal hematopoiesis is highly prevalent in blastic plasmacytoid dendritic cell neoplasm and frequently sharing a clonal origin in elderly patients

Khanlari, Mahsa; Yin, C. Cameron; Takahashi, Koichi; Lachowiez, Curtis; Tang, Guilin; Loghavi, Sanam; Bah, Ismaël; Wang, Wei; Konoplev, Sergej; Medeiros, L. Jeffrey; Pemmaraju, Naveen; Khoury, Joseph D.; Wang, Sa A.

doi:10.1038/s41375-022-01538-9

Cited by 28 publications

(28 citation statements)

References 32 publications

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“…As noted above, pDCs in pDC-AML are derived from CD34-positive blasts; in contrast, pDCs in BPDCN are believed to be derived from the CD56+ subset of pDC precursors [ 19 , 20 ]. A myeloid origin of BPDCN has been supported by a frequent association of BPDCN with myelodysplastic syndromes (MDS), CMML and MPN [ 21 , 22 , 23 , 24 ], and the recent demonstration of a shared clonal origin of BPDCN with CMML [ 24 , 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Immunophenotypic and Molecular Features of Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation Are Distinct from Blastic Plasmacytoid Dendritic Cell Neoplasm

Wang

Khoury

et al. 2022

Cancers

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Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number of pDCs in pDC-AML was 6.6% (range, 2% to 26.3%) and their immunophenotype reminiscent of pDCs in early or intermediate stages of differentiation. The immunophenotype of pDCs in pDC-AML was different from BPDCN (n = 39), with major disparities in CD34 (96% vs. 0%), CD56 (8% vs. 97%) and TCL1 (12% vs. 98%) and significant differences in frequency of CD4, CD13, CD22, CD25, CD36, CD38, CD117 and CD303 expression. At the molecular level, the genetic landscapes of pDC-AML and BPDCN also differ, with RUNX1 mutations detected in 64% of pDC-AML versus 2% of BPDCN. Disparities in TET2 (21% vs. 56%), FLT3 (23% vs. 0%), DNMT3A (32% vs. 10%) and ZRSR2 (2% vs. 16%) (all p < 0.05) were also detected. The distinct immunophenotypic and mutation profiles of pDC-AML and BPDCN indicate that the neoplastic pDCs in pDC-AML and BPDCN derived from different subsets of pDC precursors.

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Section: Discussionmentioning

confidence: 99%

Immunophenotypic and Molecular Features of Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation Are Distinct from Blastic Plasmacytoid Dendritic Cell Neoplasm

Wang

Khoury

et al. 2022

Cancers

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“…Future studies are now aimed at more comprehensive cohorts of patients with complete clinical follow-up and available samples of both tumor and, if available, unaffected blood or bone marrow samples in order to investigate the relationship of our multi-omics defined BPDCN subtypes with the emerging role of clonal hematopoiesis in BPDCN 20 .…”

Section: Discussionmentioning

confidence: 99%

“…An oncoplot integrating clinical features and mutational status of all putative oncogenic driver genes according to our MUTSIGCV analysis is provided in Figure 1A. The list of significant candidate driver genes included several genes previously implicated in BPDCN and further expanded on these 5,11,14,18,20,37,38 .…”

Section: The Mutational Landscape Of Bpdcn Identified By Wesmentioning

confidence: 99%

“…This is further reflected in the mutational features of BPDCN, comprising mutations in epigenetic regulation ( TET2, ASXL1, EZH2 ), RAS signaling ( NRAS, KRAS ), splicing ( ZRSR2, SF3B1 ) and tumor suppressors (TSGs; TP53, ATM ). Recently, mutational disruption of epigenetic regulators except RTK-RAS and TSGs was shown to be a recurrent feature of clonal hematopoiesis, frequently underlying BPDCN 20 . A comprehensive and integrative molecular characterization of a representative and clinically annotated cohort of BPDCN patients has not been performed so far.…”

Section: Introductionmentioning

confidence: 99%

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Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

Künstner

Schwarting

Witte

et al. 2022

Preprint

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy assumed to originate from plasmacytoid dendritic cells (pDCs), which mostly affects the skin, bone marrow, lymph nodes and sequentially other organ systems. RNA-, targeted- and exome sequencing studies have identified molecular characteristics, associated with BPDCN-pathogenesis, yet an integrative molecular assessment of BPDCN remains pending. Here, we combined paired WES/RNA-Seq with genome-wide copy-number analysis to characterize 47 BPDCN patients for mutational drivers, cytogenetic aberrations and gene-expression profiles. We identified alterations in epigenetic regulators (TET2, EP300, DNMT3A, SF3B1, EZH2) and a mutational disruption of RTK-RAS signaling (NF1, NRAS, EGFR) as drivers of BPDCN alongside deletions of tumor suppressors (CDKN2A, RB1, TP53), amplifications of oncogenes (IDH2, MET, EZH2) and recurrent fusions (MYB, ALK). The mutational landscape further provides evidence for frequent induction of PDGF signaling and extracellular matrix interactions as well as a gender specificity and a subset of MSIhigh patients. Many genes affected in BPDCN are shared with chronic myelomonocytic leukemia (CMML), emphasizing a close relationship between these entities and to a lesser extent with acute myeloid leukemia (AML). Ontological assessment of RNA-Seq data revealed two BPDCN subtypes, a typical pDC-derived subtype (C1) and a (common) cDC-enriched subtype (C2), which were then shown to exhibit distinct mutational (EP300, ARID2, NF1 mutations in typical pDC vs. DNMT3A, SRSF2 mutations in the cDC-enriched subtype) and clinical features. In summary, our hitherto most comprehensive characterization of BPDCN reveals molecular hallmarks alongside actionable vulnerabilities and highlights two novel subtypes that are molecularly and clinically distinct.

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“…This is reflected in myeloid mutational features of BPDCN, comprising mutations in epigenetic regulation ( TET2 , ASXL1 , EZH2 ), RAS signaling ( NRAS , KRAS ), splicing ( ZRSR2 , SF3B1 ) and tumor suppressors (TSGs; TP53 , ATM ). Recently, mutations in epigenetic regulators were shown to be a recurrent feature of clonal hematopoiesis, underlying BPDCN [ 9 ].…”

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confidence: 99%

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

et al. 2022

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Bone marrow clonal hematopoiesis is highly prevalent in blastic plasmacytoid dendritic cell neoplasm and frequently sharing a clonal origin in elderly patients

Cited by 28 publications

References 32 publications

Immunophenotypic and Molecular Features of Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation Are Distinct from Blastic Plasmacytoid Dendritic Cell Neoplasm

Immunophenotypic and Molecular Features of Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation Are Distinct from Blastic Plasmacytoid Dendritic Cell Neoplasm

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

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