PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature

Abstract

PRDM16 is a transcriptional coregulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes, and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling, and repressed inflammation, while sPrdm16 supported B cell development biased toward marginal zone B cells and induced an inflammatory signature. In a mouse model of human MLL-AF9 leukemia, fPrdm16 extended latency, while sPrdm16 shortened latency and induced a strong inflammatory signature, including several cytokines and chemokines that are associated with myelodysplasia and with a worse prognosis in human AML. Finally, in human NPM1-mutant and in MLL-translocated AML, high expression of PRDM16, which negatively impacts outcome, was associated with inflammatory gene expression, thus corroborating the mouse data. Our observations demonstrate distinct roles for Prdm16 isoforms in normal HSCs and AML, and identify sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.

Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes

“…We identified HBV integrations with high integration allele fraction seven non-recurrent cancer-related genes, including GAS7 [74,75], NS [77,78], NRG1 [79], PRDM16 [80], ARID1B [81], and AFF1 [82]. GAS7 has be directly regulated by P53 and is part of a critical mechanism that mediate metastasis [74]; NRG1 fusions were identified as drivers for lung adenoc…”

“…We identified HBV integrations with high integration allele fractions in tumors in seven non-recurrent cancer-related genes, including GAS7 [ 74 , 75 ], NSP [ 76 ], RSPO2 [ 77 , 78 ], NRG1 [ 79 ], PRDM16 [ 80 ], ARID1B [ 81 ], and AFF1 [ 82 ]. GAS7 has been shown to be directly regulated by P53 and is part of a critical mechanism that mediates breast cancer metastasis [ 74 ]; NRG1 fusions were identified as drivers for lung adenocarcinoma [ 79 ]; And the involvement of PRDM16 in leukemia [ 80 ], ARID1B in ovarian cancer [ 81 ], and AFF1 in leukemia [ 82 ] has also been reported; It has been demonstrated that a GAS7 -mediated pathway suppressed proliferation of HCC cells following treatment with oxaliplatin, an alkylating anti-neoplastic agent, and the inhibition of GAS7 negated the beneficial effects of the drug [ 83 ]. Similarly, NRG1 is associated with promoting metastasis of HCC cells by increasing epithelial-mesenchymal transition, thus increasing migratory behavior of the cancer cells [ 84 ] (genetic variants in NRG1 have also been associated with schizophrenia [ 85 ]).…”

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

“…In this study, we found that two epigenetic writers named PRDM16 and SUV39H1 had signi cant high transcriptional expressions in 50% and 36% of AML patients respectively. PRDM16 was previously detected to drive a prognostically unfavorable in ammatory signature and also to regulate the expression of cytokines and chemokines, including VEGF, HGF, and TNF in AML patients [44]. Overexpression of PRDM16 has been demonstrated in approximately 30% of AML patients, which was associated with poor prognosis [44].…”

“…PRDM16 was previously detected to drive a prognostically unfavorable in ammatory signature and also to regulate the expression of cytokines and chemokines, including VEGF, HGF, and TNF in AML patients [44]. Overexpression of PRDM16 has been demonstrated in approximately 30% of AML patients, which was associated with poor prognosis [44]. A great deal of evidence is already in hand that explores the suppressive role of SUV39H1 on TSGs in the AML patients [45].…”

Multifaceted Role of PRDM Proteins in Human Cancer

“…Moreover, these PRDM genes both codify for short and full-length protein isoforms and are mutually involved in AML rearrangements [232,242,243]. The mouse model of conditional Prdm16 deletion elucidated the role of these two isoforms in normal and leukemic hematopoiesis and identified sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia [244]. Notably, unlike the PR− isoforms, both full-length isoforms of PRDM16 and MECOM exhibited a significantly enriched association with components of the NuRD chromatin remodeling complex [245].…”