Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

Somasundaram, Rajesh; Prasad, Mahadesh A. J.; Ungerbäck, Jonas; Sigvardsson, Mikael

doi:10.1182/blood-2014-12-575688

Cited by 113 publications

(95 citation statements)

References 129 publications

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“…Interestingly, these lineage-specific transcription factors are often found to be altered in B-cell acute lymphoblastic leukemia (B-ALL). These findings highlight the plasticity of leukemia cells and how aberrant lymphoid developmental programs can favor leukemogenesis (Horcher et al 2001;Rathert et al 2015;Somasundaram and Sigvardsson 2015).…”

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confidence: 83%

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

et al. 2017

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Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell-and T-cell-specific factors. Additionally, Phf6KO cells show significant downregulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.

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confidence: 83%

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

et al. 2017

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“…Error bars indicate Ϯ S.E. modulated by PBX1, an important transcription factor extensively studied in pre-B-cell leukemia, although many transcription factors have been reported in leukemia cells and are responsible for leukemogenesis (11), such as CCAAT/enhancer-binding protein ␣ (C/EBPA) (12), SP1 (12), NF-B (13), STAT3 (14), PU.1 (15), HOX9 (16), PBX1 (9), and many others (11). PBX1 is frequently reported as a fusion protein in association with a chromosomal translocation t(1;19) involving itself and TCF3/E2A (17).…”

Section: Discussionmentioning

confidence: 99%

The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

Han

Tang

et al. 2016

Journal of Biological Chemistry

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RNF6 is a little-studied ring finger protein. In the present study, we found that RNF6 was overexpressed in various leukemia cells and that it accelerated leukemia cell proliferation, whereas knockdown of RNF6 delayed tumor growth in xenografts. To find out the mechanism of RNF6 overexpression in leukemia, we designed a series of truncated constructs of RNF6 regulatory regions in the luciferase reporter system. The results revealed that the region between ؊144 and ؊99 upstream of the RNF6 transcription start site was critical and that this region contained a PBX1 recognition element (PRE). PBX1 modulated RNF6 expression by binding to the specific PRE. When PRE was mutated, RNF6 transcription was completely abolished. Further studies showed that PBX1 collaborated with PREP1 but not MEIS1 to modulate RNF6 expression. Moreover, RNF6 expression could be suppressed by doxorubicin, a major anti-leukemia agent, via down-regulating PBX1. This study thus suggests that RNF6 overexpression in leukemia is under the direction of PBX1 and that the PBX1/RNF6 axis can be developed as a novel therapeutic target of leukemia.The ring finger protein 6 (RNF6) belongs to the largest RING ubiquitin ligase family, and it is mapped to chromosome band 13q12.2, a harbor of several critical tumor suppressor genes (1). RNF6 is believed to be a tumor suppressor because of its chromosomal location and somatic mutations in esophageal squamous cell carcinomas (2), but confirmative evidence is not available. In contrast, recent studies suggest that RNF6 is probably an oncogene. RNF6 is found at a high level in prostate cancers. As a ubiquitin ligase, RNF6 interacts with androgen receptor (AR) 3 and mediates atypical polyubiquitination chains at Lys-6 and Lys-27, thus promoting the transcriptional activity of AR by facilitating its binding to the coactivators (3). By modulating AR function, RNF6 promotes prostate cancer cell growth. In contrast, mutations and specific knockdown of RNF6 alter AR transcriptional activity and delay prostate cancer growth in xenograft models (3). RNF6 is also elevated in cisplatin-resistant human lung adenocarcinoma cells (4). Therefore, RNF6 probably plays a critical role in tumorigenesis and chemoresistance. However, the studies on RNF6 are very limited, and the biological functions and modulation of RNF6 are largely unknown.In the present study, we evaluated the RNF6 function in leukemia cells and found that RNF6 is overexpressed in leukemia cells and contributes to leukemia cell proliferation. Furthermore, RNF6 overexpression in leukemia is found to be modulated by the transcription factor PBX1, the pre-B-cell leukemia homeobox 1.

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“…4 Our model is based on tumors developing in mice carrying heterozygote mutations in the Ebf1 and Pax5 genes encoding transcription factors critical for stable B-lineage identity. 5 Genetic alterations causing reduction in the functional dose of these proteins are common in human B-ALL with mutations or deletions in about 40% of the leukemia cases 6 and knock down of PAX5 or EBF1 levels in human leukemia cells resulted in increased lineage plasticity. 7 These findings suggest that the same regulatory networks that regulate normal B-cell development may be involved both in transformation as well as in lineage conversion processes, which further highlights the importance of these transcription factors in leukemia.…”

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confidence: 99%

Cellular plasticity in B-cell leukemia

2017

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Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

Cited by 113 publications

References 129 publications

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

Cellular plasticity in B-cell leukemia

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