The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 rearrangements share singular biological features

Eveillard, Marion; Delaunay, Jacques; Richebourg, Steven; Lodé, Laurence; Garand, Richard; Wuillème, Soraya; Duhoux, François; Antoine‐Poirel, Hélène; Godon, Catherine; Béné, Marie C.

doi:10.3324/haematol.2014.121079

Cited by 7 publications

(6 citation statements)

References 12 publications

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“…These differences in latency were not caused by changes in engraftment, as 24-hour engraftment experiments showed that, in fact, fPrdm16-expressing cells engrafted more efficiently than sPrdm16-expressing cells (Figure 6C). Cytological analysis showed increased fragmented nuclei in cells expressing sPrdm16 (Supplemental Figure 8, I and J), a finding consistent with the dysplastic changes observed in AML with Prdm16 translocations (5,6,18,28,32,33), where the PR domain is deleted. sPrdm16-expressing cells also included fewer cycling cells than those expressing fPrdm16 or empty vector (Figure 6D).…”

Section: Resultssupporting

confidence: 79%

“…In translocations involving PRDM16, the PR domain is often deleted (6,7,18,22,27), and sometimes only sPRDM16 is expressed (27). These leukemias show dysplastic features and are associated with poor survival (31)(32)(33). Similarly, leukemic translocations involving the closely related family member PRDM3 (MDS1/EVI1) delete the PR domain (17,18).…”

Section: Resultsmentioning

confidence: 99%

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

Corrigan¹,

Luchsinger²,

Almeida³

et al. 2018

Journal of Clinical Investigation

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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.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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

Corrigan¹,

Luchsinger²,

Almeida³

et al. 2018

Journal of Clinical Investigation

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“…Inv(3) and other MECOM rearrangements such as t(3;6) or t(2;3) that involved relatively small segments might not be detected by CBA, especially if the quality of specimen is suboptimal. Other authors have suggested that the presence of monosomy 7, which is the most frequent additional abnormality to MECOM , or the clinical features associated with 3q21q26 syndrome may require the investigation of MECOM by FISH analysis (Shearer et al, ; Eveillard et al, ).…”

Section: Discussionmentioning

confidence: 99%

Complex chromosomal rearrangements leading to MECOM overexpression are recurrent in myeloid malignancies with various 3q abnormalities

Baldazzi

Luatti

Zuffa

et al. 2016

Genes Chromosomes & Cancer

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Chromosomal rearrangements involving 3q26 are recurrent findings in myeloid malignancies leading to MECOM overexpression, which has been associated with a very poor prognosis. Other 3q abnormalities have been reported and cryptic MECOM rearrangements have been identified in some cases. By fluorescence in situ hybridization (FISH) analysis, we investigated 97 acute myeloid leukemia/myelodysplastic syndrome patients with various 3q abnormalities to determine the role and the frequency of the involvement of MECOM. We identified MECOM rearrangements in 51 patients, most of them showed 3q26 involvement by chromosome banding analysis (CBA): inv(3)/t(3;3) (n = 26) and other balanced 3q26 translocations (t(3q26)) (n = 15); the remaining cases (n = 10) showed various 3q abnormalities: five with balanced translocations involving 3q21 or 3q25; two with homogenously staining region (hsr) on 3q; and three with other various 3q abnormalities. Complex rearrangements with multiple breakpoints on 3q, masking 3q26 involvement, were identified in cases with 3q21/3q25 translocations. Furthermore, multiple breaks were observed in two cases with t(3q26), suggesting that complex rearrangement may also occur in apparently simple t(3q26). Intrachromosomal gene amplification was another mechanism leading to MECOM overexpression in two cases with hsr on 3q. In the last three cases, FISH analysis revealed 3q26 involvement that was missed by CBA because of metaphases' suboptimal quality. All cases with MECOM rearrangements showed overexpression by real-time quantitative PCR. Finally, MECOM rearrangements can occur in patients with 3q abnormalities even in the absence of specific 3q26 involvement, underlining that their frequency is underestimated. As MECOM rearrangement has been associated with very poor prognosis, its screening should be performed in patients with any 3q abnormalities.

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“…For instance, PRDM16 is also a common target site for viral integration [239][240][241]. 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].…”

Section: Prdm16mentioning

confidence: 99%

Multifaceted Role of PRDM Proteins in Human Cancer

Casamassimi

Rienzo

Zazzo

et al. 2020

IJMS

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The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.

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The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 rearrangements share singular biological features

Cited by 7 publications

References 12 publications

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

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

Complex chromosomal rearrangements leading to MECOM overexpression are recurrent in myeloid malignancies with various 3q abnormalities

Multifaceted Role of PRDM Proteins in Human Cancer

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