Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity

Hervé, Maxime; Xu, Kai; Ng, Yen Shing; Wardemann, Hedda; Albesiano, Emilia; Messmer, Bradley T.; Chiorazzi, Nicholas; Meffre, Eric

doi:10.1172/jci24387

Cited by 294 publications

(323 citation statements)

References 44 publications

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“…5 Two lines of evidence suggest that LPL might indeed be regulated by BCR activation in vivo: first, LPL expression in vivo is almost exclusively seen in IgV H -unmutated CLL, which are associated with autoreactive BCR activity; 5 second, we demonstrate here that LPL is induced or significantly increased by BCR stimulation ex vivo. Therefore, LPL expression has to be determined as a prerequisite feature of CLL cells.…”

Section: Discussionmentioning

confidence: 56%

“…2 A major factor in the pathogenesis of CLL is the microenvironment of the leukemic cell, 3 especially the role of antigenic stimulation via the B-cell receptor (BCR). 4 An unmutated status of the IgV H gene was shown to exhibit enhanced autoreactivity 5 and to predict an unfavorable prognosis in CLL. 6 Furthermore, expression of ZAP-70 is associated with an enhanced signal transduction via the BCR complex.…”

Section: Introductionmentioning

confidence: 99%

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Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2007

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Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5 þ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5 þ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n ¼ 26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a halfmaximal dose (IC 50 ) of 2.35 lM. In healthy B cells a significantly higher mean IC 50 of 148.5 lM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; Po0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P ¼ 0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2007

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“…From a biological standpoint, there are data to suggest that low mutational load in CLL productive rearrangements (leading to a germline identity of X98% but o100%) may have been functionally selected, perhaps providing the clone with certain antigenic reactivities. [15][16][17] The unproductive rearrangement would have been similarly targeted by the SHM process but remained free of any functional constraints and thus left to acquire significantly more mutations of a random nature. Whatever the underlying explanation for this phenomenon, at present, a prognostically relevant interpretation is lacking.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

et al. 2011

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Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.

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“…Such similarity of BCR structure may be particularly important for CLL cases with progressive disease where the leukemic cells bear unmutated immunoglobulin heavy chain variable (IgHV) genes [unmutated-CLL (UM-CLL)]. In these cases, the expressed BCR is poly-reactive and binds to a variety of self and foreign antigens (6). Work by Krysov and colleagues (7) has shown that the BCR expressed on CLL cells, particularly from patients with UM-CLL, shows features that are associated with continuous in vivo exposure to antigen, whereas others have shown that such continuous BCR-stimulation is reflected in the pattern of gene expression observed in freshly isolated cells (8).…”

Section: Introductionmentioning

confidence: 99%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity

Cited by 294 publications

References 44 publications

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

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