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PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature
David J. Corrigan, … , Alexandros Strikoudis, Hans-Willem Snoeck
David J. Corrigan, … , Alexandros Strikoudis, Hans-Willem Snoeck
Published June 7, 2018
Citation Information: J Clin Invest. 2018;128(8):3250-3264. https://doi.org/10.1172/JCI99862.
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Research Article Hematology Article has an altmetric score of 2

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

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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.

Authors

David J. Corrigan, Larry L. Luchsinger, Mariana Justino de Almeida, Linda J. Williams, Alexandros Strikoudis, Hans-Willem Snoeck

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Figure 7

PRDM16 is associated with an inflammatory signature in a subset of human AML.

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PRDM16 is associated with an inflammatory signature in a subset of huma...
(A) Correlation between PRDM16 RPKM and overall survival in all 179 human AML samples from the Cancer Genome Atlas (CGA) (n = 179). (B) PRDM16 RPKM for all samples from A, ranked by RPKM, illustrating Q1/Q2 (PRDM16lo) and Q4 (PRDM16hi). (C) Principal component (PC) analysis of cohorts described in B. (D) PRDM16 RPKM compared within 4 mutually exclusive groups from the CGA AML cohort: NPM1 mutated, NPM1wt HOXA9/B4 double-positive (HOXA/B), HOXA9 or HOXB4 single-positive (One HOX), and HOXA9/HOXB4 double-negative (No HOX) (n = 179). (E and F) Correlation between PRDM16 RPKM and overall survival among NPM1-mutated AML samples (n = 47) (E) and MLL-rearranged AML samples (F) in the CGA (n = 21). (G and H) Principal component analysis of NPM1-mutated (G) and MLL-rearranged (H) AML cases from the CGA, comparing PRDM16hi and PRDM16lo cohorts. (I and J) Representative list of GO pathways upregulated in PRDM16hi or PRDM16lo cohorts of NPM1-mutated (I) or MLL-rearranged (J) AML cases in the CGA. Values expressed as –log10 of the P value, determined by PANTHER analysis. (K) χ2 analysis of observed versus expected number of dysregulated MDS-related genes in common with genes from our RNA-Seq analysis in Figure 5H and Figure 6E. Data represent mean ± SEM. NS, P > 0.05; *P < 0.05; **P < 0.01; Pearson’s test for linear correlations, 1-way ANOVA for multiple comparisons, χ2 test for comparing observed vs. expected values.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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