Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response
Abstract:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYCBPDCN (positive for rearrangement and expression) and 59 (54%) MYCBPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significa… Show more
“…1c). Notably, a recent study reported that 22 out of 118 BPDCN patients harbored t(6;8) and enhanced expression of MYC, compared to BPDCN cells without t(6;8) 8 . Therefore, the expression of MYC are increased in BPDCN cells harboring t(6;8).Fig.…”
Section: Resultsmentioning
confidence: 99%
“…TP53 and CDKN2A ), and loss-of-function mutations in epigenetic modifiers (e.g. TET2 ) 4 , which are commonly mutated in myeloid malignancies 5 , whereas chromosomal translocation (6;8)(p21;q24) was exclusively observed in patients with BPDCN 6–8 .…”
Section: Introductionmentioning
confidence: 99%
“…IgH- MYC in lymphoma, TCR- LMO2 in T-ALL) 15,26 . Previous studies reported that t(6;8)(p21;q24) involved adjacent regions to MYC and RUNX2 in the cells of BPDCN patients; 7,8,27 however, the biological function of t(6;8) currently remains unclear. Based on these findings, we successfully demonstrated that t(6;8) juxtaposed the MYC and pDC-specific RUNX2 super-enhancer in BPDCN cells.…”
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of
RUNX2
is associated with the
MYC
promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific
RUNX2
super-enhancer is hijacked to activate
MYC
in addition to
RUNX2
expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of
MYC
and
RUNX2
is sufficient to initiate the transformation of BPDCN in mice lacking
Tet2
and
Tp53
, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.
“…1c). Notably, a recent study reported that 22 out of 118 BPDCN patients harbored t(6;8) and enhanced expression of MYC, compared to BPDCN cells without t(6;8) 8 . Therefore, the expression of MYC are increased in BPDCN cells harboring t(6;8).Fig.…”
Section: Resultsmentioning
confidence: 99%
“…TP53 and CDKN2A ), and loss-of-function mutations in epigenetic modifiers (e.g. TET2 ) 4 , which are commonly mutated in myeloid malignancies 5 , whereas chromosomal translocation (6;8)(p21;q24) was exclusively observed in patients with BPDCN 6–8 .…”
Section: Introductionmentioning
confidence: 99%
“…IgH- MYC in lymphoma, TCR- LMO2 in T-ALL) 15,26 . Previous studies reported that t(6;8)(p21;q24) involved adjacent regions to MYC and RUNX2 in the cells of BPDCN patients; 7,8,27 however, the biological function of t(6;8) currently remains unclear. Based on these findings, we successfully demonstrated that t(6;8) juxtaposed the MYC and pDC-specific RUNX2 super-enhancer in BPDCN cells.…”
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of
RUNX2
is associated with the
MYC
promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific
RUNX2
super-enhancer is hijacked to activate
MYC
in addition to
RUNX2
expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of
MYC
and
RUNX2
is sufficient to initiate the transformation of BPDCN in mice lacking
Tet2
and
Tp53
, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.
“…It is interesting to note that historically, the relationship between the nucleolus and cancer has been discussed because the number and shape of nucleoli are altered in almost any type of cancer cell. An enlarged and prominent nucleolus is one of the indicators of cancer diagnoses in histopathology (Montanaro et al 2008;Sakamoto et al 2018). Such a phenomenon might indicate that a cancerspecific nuclear environment affects or induces the function and assembly/disassembly of condensates inside cancer cells.…”
Section: The Formation and Regulation Of Membrane-less Cellular Organmentioning
Progress in development of biophysical analytic approaches has recently crossed paths with macromolecule condensates in cells. These cell condensates, typically termed liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. However, the detailed biophysical processes within the cell that lead to these assemblies remain largely unexplored. In this review, we evaluate recent discoveries related to biological phase separation including stress granule formation, chromatin regulation, and processes in the origin and evolution of life. We also discuss the potential issues and technical advancements required to properly study biological phase separation.
“…2 For example, changes in composition, number, size and activity on nucleoli are seen, and their diagnostic significance has been proposed 47,48 The prominent nucleolus observed in a rare hematological malignancy, blastic plasmacytoid dendritic cell neoplasm, is a compelling case. 49 Another relevant alteration is found in the PML body, in which the level of SUMOylation may underlie LLPS. 50 In acute promyelocytic leukemia (APL), heterozygotic chromo-…”
Section: Nucle Ar Microenvironments Are Altered In C An Cer Smentioning
The eukaryotic nucleus is not a homogenous single‐spaced but a highly compartmentalized organelle, partitioned by various types of membraneless structures, including nucleoli, PML bodies, paraspeckles, DNA damage foci and RNA clouds. Over the past few decades, these nuclear structures have been implicated in biological reactions such as gene regulation and DNA damage response and repair, and are thought to provide “microenvironments,” facilitating these reactions in the nucleus. Notably, an altered morphology of these nuclear structures is found in many cancers, which may relate to so‐called “nuclear atypia” in histological examinations. While the diagnostic significance of nuclear atypia has been established, its nature has remained largely enigmatic and awaits characterization. Here, we review the emerging biophysical principles that govern biomolecular condensate assembly in the nucleus, namely, liquid‐liquid phase separation (LLPS), to investigate the nature of the nuclear microenvironment. In the nucleus, LLPS is typically driven by multivalent interactions between proteins with intrinsically disordered regions, and is also facilitated by protein interaction with nucleic acids, including nuclear non–coding RNAs. Importantly, an altered LLPS leads to dysregulation of nuclear events and epigenetics, and often to tumorigenesis and tumor progression. We further note the possibility that LLPS could represent a new therapeutic target for cancer intervention.
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