The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell–intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma–derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus–like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL–RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell–intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.

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The PI3K∂-Selective Inhibitor Idelalisib Induces T- and NK-Cell Dysfunction Independently of B-Cell Malignancy-Associated Immunosuppression

Frontiers in Immunology ◽

10.3389/fimmu.2021.608625 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lisa Rohrbacher ◽

Bettina Brauchle ◽

Ana Ogrinc Wagner ◽

Michael von Bergwelt-Baildon ◽

Veit L. Bücklein ◽

...

Keyword(s):

B Cell ◽

Nk Cells ◽

Nk Cell ◽

Selective Inhibitor ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Potential Contribution ◽

B Cell Malignancy ◽

Increased Risk ◽

Cell Malignancy

B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of these pathways results in resistance to apoptosis and enhanced survival of the leukemic cells. Idelalisib is a highly selective inhibitor of the PI3K p110∂ isoform and is approved for the treatment of CLL in patients with relapsed/refractory disease or in those harboring 17p deletions or tp53 mutations. Despite the initial excitement centered around high response rates in clinical trials of idelalisib, its therapeutic success has been hindered by the incidence of severe opportunistic infections. To examine the potential contribution of idelalisib to the increased risk of infection, we investigated the effects of idelalisib on the immune cell compartments of healthy donors (HDs) and CLL patients. PI3K∂ blockade by idelalisib reduced the expression levels of inhibitory checkpoint molecules in T cells isolated from both HDs and CLL patients. In addition, the presence of idelalisib in cultures significantly decreased T-cell-mediated cytotoxicity and granzyme B secretion, as well as cytokine secretion levels in both cohorts. Furthermore, idelalisib reduced the proliferation and cytotoxicity of HD NK cells. Collectively, our data demonstrate that both human T and NK cells are highly sensitive to PI3K∂ inhibition. Idelalisib interfered with the functions of T and NK cell cells from both HDs and CLL patients. Therefore, idelalisib might contribute to an increased risk of infections regardless of the underlying B-cell malignancy.

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Monoclonal Gammopathy (MG) Associated with Gaucher Disease (GD). Report of 16 Cases from the French Observatoire on Gaucher Disease (FROG Study).

Blood ◽

10.1182/blood.v108.11.5004.5004 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5004-5004

Author(s):

Bernard Grosbois ◽

Jean Leone ◽

Fabrice Camou ◽

Florence Dalbies ◽

Jean Robert Harle ◽

...

Keyword(s):

General Population ◽

B Cell ◽

Gaucher Disease ◽

Bone Marrow Aspiration ◽

Lymphocytic Leukemia ◽

Imaging Data ◽

Enzyme Replacement ◽

Non Hodgkin Lymphoma ◽

B Cell Malignancy ◽

Cell Malignancy

Abstract In addition to its common bone and visceral manifestations GD is frequently associated with B cell proliferation leading possibly to MG. The objective of our study was to determine the frequency and presentation of MG in GD patients. Material and methods. FROG is a cross-sectionnal epidemiological study on adult GD involving 64 French centers. Standard clinical, biological(including serum protein electrophoresis) and imaging data performed as part of usual management within the 3 previous years were collected at the time of a routine visit. In patients with suspected MG specific additionnal data were studied:immunofixation, dosage of immunoglobulins, bone marrow aspiration. Results. From 05/2005 to 06/2006 seventy seven adult GD type 1(38 male,39 female;mean age 47.3 years, range 18 to 78 years) were included. Sixteen cases of MG(20.8%) were observed (10 male and 6 female;mean age 61.25 years, range 47 to 79 years). Mean age of 61 cases of GD without MG(43.8 years;range 18 to 70 years)was significantly lower(p<0.0001). Thirteen cases(17%)were classified as MGUS and 3 (3.8%) as B cell malignancy:1 multiple myeloma, 1 Chronic Lymphocytic Leukemia, 1 Non Hodgkin Lymphoma. In 3 cases MG and GD were diagnosed simultaneously. In 13 cases MG was diagnosed in the course of GD(mean interval 12.2 years;range 6.7 to 16 years). MG immunochemical typing revealed 75 % Ig G, 12.5 %Ig A, 12.5 %Ig M, 75 % Kappa and 25 % Lambda. We observed one biclonal gammopathy(IgG and IgA Kappa). One case of MGUS was associated with capillary leak syndrome. In two patients MG level decreased with enzyme replacement therapy. Conclusion. Frequency of MG in GD observed in our study (20.8%)is largely higher than in general population (1%). Furthermore this frequency is higher than in previous series of GD. However in GD patients, as observed in general population, frequency of MG seems to be related to age as mean age of patients with MG is significantly higher than mean age of patients without MG. Finally these data assess the need of specific follow-up regarding the high frequency of MG and the risk of B cell malignancy in GD patients.

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Predicting Clinical Outcome in B-Chronic Lymphocytic Leukemia

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.145 ◽

2012 ◽

pp. 394-398

Author(s):

Neil E. Kay

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Early Stage ◽

Response To Therapy ◽

Lymphocytic Leukemia ◽

Prognostic Models ◽

B Cell Malignancy ◽

Duration Of Response ◽

Current Therapies ◽

Progression Risk

Overview: B-Chronic lymphocytic leukemia (CLL) is a relatively common B-cell malignancy that has a very heterogeneous clinical course, despite carrying the designation of “chronic,” which is a gross oversimplification. Being able to give some estimate of the rates of disease progression and overall survival (OS) at first diagnosis is, therefore, important in CLL. The ability to accurately predict response to therapy, as well as subsequent duration of response to therapy, is required given the variability of current therapies to induce and sustain treatment responses. The holy grail of prognostics would be to state with accuracy which therapy or types of therapy are best for a given patient. Although there is no complete answer to prognostic counseling, there is a continued development of markers specific to the CLL B cell and/or to its environment, as well as of testing of prognostic models. These models use both traditional and novel prognostic markers that can aid in the dissection of outcome for early-stage CLL in terms of progression risk and time to therapy. This has resulted in significant enhancement of our ability to guide and predict outcome for our patients with CLL.

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Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.0822 ◽

2017 ◽

Vol 35 (9) ◽

pp. 984-993 ◽

Cited By ~ 29

Author(s):

Gregory Lazarian ◽

Romain Guièze ◽

Catherine J. Wu

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

New Era ◽

Sequencing Technologies ◽

B Cell Malignancy ◽

Future Drug ◽

Indolent Disease

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter- and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein.

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