The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia

Li, Yan; Hu, Shimin; Wang, Sa A.; Li, Shaoying; Huh, Yang O.; Tang, Zhenya; Medeiros, L. Jeffrey; Tang, Guilin

doi:10.1038/modpathol.2016.35

Cited by 17 publications

(13 citation statements)

References 25 publications

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“…MYC rearrangements in CLL are also associated with histological progression or large cell transformation (Richter syndrome) (Fabbri et al, 2011; Li et al, 2016; Rossi et al, 2011). NOTCH1 mutations and MYC rearrangements tend to be mutually exclusive in Richter syndrome (Fabbri et al, 2011), suggesting that both may serve to produce sustained MYC expression.…”

Section: Discussionmentioning

confidence: 99%

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

et al. 2017

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Summary Gain-of-function Notch mutations are recurrent in mature small B-cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B-cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This unique B-cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B-cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B-cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.

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Section: Discussionmentioning

confidence: 99%

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

et al. 2017

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“…The frequency of c-MYC rearrangement in CLL/SLL varies greatly in different studies. Nelson et al showed no c-MYC rearrangement by FISH in 109 cases of CLL/SLL [156], and Li et al identified 0.7% CLL/SLL with 8q24/MYC rearrangement in approximately 4500 cases [157]. In Li’s study, c-MYC is most frequently rearranged with immunoglobulin heavy chain gene locus in the t(8;14)(q24·1;q32), followed by light chain loci in t(8;22)(q24·1;q11·2), or t(2;8)(p12;q24·1).…”

Section: C-myc In Low Grade B-cell Lymphomasmentioning

confidence: 99%

“…In Li’s study, c-MYC is most frequently rearranged with immunoglobulin heavy chain gene locus in the t(8;14)(q24·1;q32), followed by light chain loci in t(8;22)(q24·1;q11·2), or t(2;8)(p12;q24·1). c-MYC rearrangement in CLL/SLL is often acquired during the course of disease and is associated with increased prolymphocytes or Richter’s transformation [157,158]. c-MYC rearrangement is frequently seen with concomitant adverse cytogenetic markers of CLL/SLL, such as del(11q) and/or del(17p)/monosomy 17, which helps explain the poor clinical outcomes in these patients [159].…”

Section: C-myc In Low Grade B-cell Lymphomasmentioning

confidence: 99%

“…However, the clinical significance of c-MYC rearrangement in CLL/SLL is likely dependent on the karyotype. If present in a non-complex karyotype, patients usually respond well to risk-adapted therapies and can achieve remission, while cases with a complex karyotype often show Richter’s transformation and an aggressive and refractory clinical course [157]. In a cohort of 156 patients with B-cell neoplasms harboring c -MYC rearrangement 33 patients (21%) carried the diagnosis of CLL.…”

Section: C-myc In Low Grade B-cell Lymphomasmentioning

confidence: 99%

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The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects

Nguyen

Papenhausen

Shao

2017

Genes

141

101

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c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC dysregulation induces lymphomagenesis by loss of the tight control of c-MYC expression, leading to overexpression of intact c-MYC protein, in contrast to the somatic mutations or fusion proteins seen in many other oncogenes. Dysregulation of c-MYC in B-cell lymphomas occurs either as a primary event in Burkitt lymphoma, or secondarily in aggressive lymphomas such as diffuse large B-cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma, or double-hit lymphoma. Secondary c-MYC changes include gene translocation and gene amplification, occurring against a background of complex karyotype, and most often confer aggressive clinical behavior, as evidenced in the double-hit lymphomas. In low-grade B-cell lymphomas, acquisition of c-MYC rearrangement usually results in transformation into highly aggressive lymphomas, with some exceptions. In this review, we discuss the role that c-MYC plays in the pathogenesis of B-cell lymphomas, the molecular alterations that lead to c-MYC dysregulation, and their effect on prognosis and diagnosis in specific types of B-cell lymphoma.

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“…Absence of del(13q14) also has been associated with an increased risk for transformation to RS. Rearrangements involving the MYC locus (8q24), very rare in CLL/SLL, may be gained during the course of disease, and have been suggested as a secondary event in disease progression, particularly in patients who harbor 8q24/MYC rearrangement in the context of a complex karyotype [12,38]. Another possible mechanism of MYC involvement in CLL/ SLL, also associated with a shorter clinical course, is 8q24/MYC amplification.…”

Section: Histologic Variants Of Richter Transformationmentioning

confidence: 99%

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

et al. 2016

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Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo transformation to a clinically aggressive lymphoma. The most common form of transformation, to DLBCL, is also known as Richter syndrome. Transformation determines the course of the disease and is associated with unfavorable patient outcome. Precise detection of transformation and identification of predictive biomarkers and specific molecular pathways implicated in the pathobiology of transformation in CLL/SLL will enable personalized therapeutic approach and provide potential avenues for improving the clinical outcome of patients. In this review, we present an overview of the pathologic features, risk factors, and pathogenic mechanisms of CLL/ SLL transformation.

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The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia

Cited by 17 publications

References 25 publications

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

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