Genomic loss of the putative tumor suppressor gene <i>E2A</i> in human lymphoma

Steininger, Anne; Möbs, Markus; Ullmann, Reinhard; Köchert, Karl; Kreher, Stephan; Lamprecht, Björn; Anagnostopoulos, Ioannis; Hummel, Michael; Richter, Julia; Beyer, Marc; Janz, Martin; Klemke, Claus‐Detlev; Stein, Harald; Dörken, Bernd; Sterry, Wolfram; Schröck, Evelin; Mathas, Stephan; Assaf, Chalid

doi:10.1084/jem.20101785

Cited by 42 publications

(80 citation statements)

References 40 publications

(67 reference statements)

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“…In contrast, heterozygous loss of the entire E2A locus is common in Sézary syndrome (20), a subtype of T cell lymphoma. None of the patients included in this study (10 to 40 years of age) have had lymphomas or infections that are typical of T cell defects.…”

Section: Resultsmentioning

confidence: 99%

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

Boisson¹,

Wang²,

Bosompem³

et al. 2013

J. Clin. Invest.

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IntroductionApproximately 85% of patients with early onset of infections, panhypogammaglobulinemia, and less than 2% CD19 + B cells in the peripheral circulation have X-linked agammaglobulinemia (1). This disorder is caused by mutations in Bruton tyrosine kinase (BTK) (2), a cytoplasmic tyrosine kinase that is activated by crosslinking of the pre-B cell and B cell antigen receptors (BCRs) (3). An additional 5%-7% of patients have rare autosomal recessive defects in components of the pre-BCR or BCR or in the downstream scaffold molecule B cell linker protein (BLNK) (4, 5). These genetic disorders all result in a block in B cell differentiation at the pro-B cell to pre-B cell transition, the stage at which the pre-B cell receptor is first expressed.We have recently described a group of 4 unrelated patients, 2 males and 2 females, with agammaglobulinemia and a very small number of B cells characterized by the lack of a BCR, but increased expression of CD19 (6). Bone marrow studies from these patients demonstrated a profound reduction in the number of CD19 + cells and a block in B cell differentiation at the common lymphoid precursor to pro-B cell stage of differentiation, a stage earlier than that seen in patients with BTK deficiency or mutations in components of the BCR signaling pathway.None of the 4 patients had a family history of immunodeficiency ( Figure 1A) or belonged to isolated populations or consanguineous families; therefore, we hypothesized that these

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Section: Resultsmentioning

confidence: 99%

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

Boisson¹,

Wang²,

Bosompem³

et al. 2013

J. Clin. Invest.

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“…Hence, a hyperactive Notch1 allele (NICD; hereafter referred to as the Notch1 oncogene) is shown to cause an exhaustion of HSCs at the expanse of T-LSCs [20]. Once transformed, LICs in Notch1-induced T-ALL depend on continued Notch1 signals for maintenance [15,[21][22][23] and on several downstream effectors that include Hes1 [24][25][26][27][28] and Myc [27,29]. These LICs were found in the immature single positive (ISP8) population, raising the question whether or not ISP8 are the cell of origin of T-ALL.…”

Section: Introductionmentioning

confidence: 99%

SCL, LMO1 and NOTCH1 reprogram thymocytes into self-renewing cells

Gerby

2014

Experimental Hematology

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The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non-malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL-LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligandindependent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self-renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co-expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL.

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“…A recurrent gene deletion is found in E2A in 70% of patients with Sezary syndrome, a type of T cell lymphoma, which is the first report demonstrating inactivating alterations in the E2A gene in human lymphomas [94]. This gene deletion results in upregulation of the cell cycle regulator Cdk6, which is a known E47 target [93] and can execute the anti-apoptotic and proliferative effects of NOTCH in these tumors.…”

Section: Tumor Suppressive Roles Of E2a In T Cell Lymphomasmentioning

confidence: 93%

“…The authors propose that one copy of E2A is necessary for the survival of these cells, and therefore homozygous mutations are selected against. The remaining copy of WT E2A may also be posttranslationally degraded by NOTCH1 [94].…”

Section: Tumor Suppressive Roles Of E2a In T Cell Lymphomasmentioning

confidence: 99%

“…Independent of the tumor suppressor roles of E2A observed in T-ALL, it was observed that E2A-deficient mice exhibit an early block in T cell development and develop lymphomas derived from immature DP or SP thymocytes [89,90,94]. Tumors, but not premalignant cells, overexpress c-Myc, which can possibly be explained by the gain of an extra copy of chromosome 15.…”

Section: Tumor Suppressive Roles Of E2a In T Cell Lymphomasmentioning

confidence: 99%

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Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

Roy

Zhuang

2018

Front. Med.

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A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt's lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

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Genomic loss of the putative tumor suppressor gene E2A in human lymphoma

Abstract: Loss of E2A, observed in more than 70% of patients with Sézary syndrome, which is a subtype of T cell lymphoma, results in altered expression of genes potentially relevant to oncogenesis.

Cited by 42 publications

References 40 publications

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCRâ€“ B cells

SCL, LMO1 and NOTCH1 reprogram thymocytes into self-renewing cells

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

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