<i>BRAF</i>mutations in chronic lymphocytic leukemia

Jebaraj, Billy Michael Chelliah; Kienle, Dirk; Bühler, Andreas; Winkler, Dirk; Döhner, Hartmut; Stilgenbauer, Stephan; Zenz, Thorsten

doi:10.3109/10428194.2012.742525

Cited by 48 publications

(48 citation statements)

References 27 publications

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“…15 In agreement with previous data, 15,16,21 sorafenib-induced cell death in primary human CLL cells was followed by downregulation of pErk ( Figures 5C and 6A). Surprisingly, but also in agreement with previous studies, 47 we did not observe an enhanced cell death after treatment with PLX4720, the tool compound for vemurafenib, 48 or after treatment with the MEK inhibitor U0126. These observations can be explained in light of recent literature.…”

Section: Discussionsupporting

confidence: 93%

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

Yaktapour

Übelhart

Schüler

et al. 2013

Blood

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Section: Discussionsupporting

confidence: 93%

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

Yaktapour

Übelhart

Schüler

et al. 2013

Blood

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“…In CLL, BRAF mutations target amino acids located in the P-loop of the kinase (Supplementary Table S4; ref. 22), leading to weaker activation than the canonical V600E mutations (18). Ectopic expression of the CLL-mutant BRAF-G469R in Ba/F3 cells showed a constitutive ERK phosphorylation and Egr2 transcription ( Fig.…”

Section: Deregulation Of Bcr Signaling As a Phenotypic Convergence Ofmentioning

confidence: 99%

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

et al. 2014

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Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE:The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088-1101

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“…The BRAF‐ V600E mutation constitutively activates BRAF by autophosphorylation of the protein and downstream MEK‐ERK signaling pathway, leading to increased expression of genes involved in survival and proliferation. BRAF ‐V600E has not been identified in other B‐cell chronic lymphoproliferative disorders12 except a few cases of CLL13 and multiple myeloma. The mutation is now considered as the molecular hallmark of the disease and represents a novel diagnostic possibility and option for therapeutic targeting of BRAF, using BRAF inhibitors.…”

Section: What Has Recently Improved the Understanding Of Hcl And Hcl‐mentioning

confidence: 99%

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

Troussard

Cornet

2017

American J Hematol

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Disease overviewHairy cell leukemia (HCL) and HCL‐like disorders, including HCL variant (HCL‐V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B‐cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.DiagnosisDiagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.Risk stratificationProgression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4‐34 positive HCL cases are associated with poor prognosisRisk adapted therapyPurine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option.Management of progressive or refractory diseaseIt is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.

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BRAFmutations in chronic lymphocytic leukemia

Cited by 48 publications

References 27 publications

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

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