Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?

Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.

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Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia

Journal of Oncology Practice ◽

10.1200/jop.2017.023291 ◽

2017 ◽

Vol 13 (6) ◽

pp. 371-377 ◽

Cited By ~ 10

Author(s):

Jennifer Edelmann ◽

John G. Gribben

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Clinical Investigation ◽

Treatment Options ◽

Treatment Strategies ◽

Clinical Trial Data ◽

Cell Receptor ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Chromosome 17

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

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Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2008-02-139139 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4665-4674 ◽

Cited By ~ 39

Author(s):

Livio Trentin ◽

Martina Frasson ◽

Arianna Donella-Deana ◽

Federica Frezzato ◽

Mario A. Pagano ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Molecular Mechanisms ◽

Catalytic Domain ◽

Cell Receptor ◽

Hsp90 Inhibitor ◽

Lymphocytic Leukemia ◽

Early Event ◽

Downstream Signaling ◽

Transient Interactions

Abstract Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B-cell receptor to downstream signaling. In B-CLL cells, Lyn is overexpressed, anomalously present in the cytosol, and displays a high constitutive activity, compared with normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600-kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL.

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Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03910-x ◽

2021 ◽

Author(s):

Sarah Wilmore ◽

Karly-Rai Rogers-Broadway ◽

Joe Taylor ◽

Elizabeth Lemm ◽

Rachel Fell ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Mrna Translation ◽

Cell Receptor ◽

Memory B Cells ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Mrna Levels ◽

Mrna Stabilization

AbstractSignaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

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Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽

10.1182/blood-2003-12-4312 ◽

2004 ◽

Vol 103 (12) ◽

pp. 4389-4395 ◽

Cited By ~ 286

Author(s):

Freda K. Stevenson ◽

Federico Caligaris-Cappio

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Cell Of Origin ◽

Regulatory B Cell ◽

V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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B-cell receptor signaling in chronic lymphocytic leukemia leans on Lyn

Leukemia & Lymphoma ◽

10.3109/10428194.2012.754097 ◽

2013 ◽

Vol 54 (6) ◽

pp. 1125-1126 ◽

Cited By ~ 2

Author(s):

Yair Herishanu ◽

Aaron Polliack

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Receptor Signaling ◽

B Cell Receptor Signaling ◽

Cell Receptor Signaling

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Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia

Haematologica ◽

10.3324/haematol.2014.106054 ◽

2014 ◽

Vol 99 (11) ◽

pp. 1722-1730 ◽

Cited By ~ 7

Author(s):

A.-C. Bergh ◽

C. Evaldsson ◽

L. B. Pedersen ◽

C. Geisler ◽

K. Stamatopoulos ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

Receptor Response

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Role of NFAT in Chronic Lymphocytic Leukemia and Other B-Cell Malignancies

Frontiers in Oncology ◽

10.3389/fonc.2021.651057 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ilenia Sana ◽

Maria Elena Mantione ◽

Piera Angelillo ◽

Marta Muzio

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Therapeutic Potential ◽

Cell Receptor ◽

Distinct Pattern ◽

B Cell Receptor ◽

Lymphocytic Leukemia ◽

B Cell Malignancies ◽

Activated T Cells ◽

Inflammatory Microenvironment

In recent years significant progress has been made in the clinical management of chronic lymphocytic leukemia (CLL) as well as other B-cell malignancies; targeting proximal B-cell receptor signaling molecules such as Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3Kδ) has emerged as a successful treatment strategy. Unfortunately, a proportion of patients are still not cured with available therapeutic options, thus efforts devoted to studying and identifying new potential druggable targets are warranted. B-cell receptor stimulation triggers a complex cascade of signaling events that eventually drives the activation of downstream transcription factors including Nuclear Factor of Activated T cells (NFAT). In this review, we summarize the literature on the expression and function of NFAT family members in CLL where NFAT is not only overexpressed but also constitutively activated; NFAT controls B-cell anergy and targeting this molecule using specific inhibitors impacts on CLL cell viability. Next, we extend our analysis on other mature B-cell lymphomas where a distinct pattern of expression and activation of NFAT is reported. We discuss the therapeutic potential of strategies aimed at targeting NFAT in B-cell malignancies not overlooking the fact that NFAT may play additional roles regulating the inflammatory microenvironment.

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B-cell receptor stereotyped subsets and outcome for patients with chronic lymphocytic leukemia in the HOVON 68 trial

10.20517/jtgg.2021.03 ◽

2021 ◽

Author(s):

Fie J. Vojdeman ◽

Lone B. Pedersen ◽

Doreen te Raa ◽

Vesa Juvonen ◽

Yvette van Norden ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Lymphocytic Leukemia

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An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cancers ◽

10.3390/cancers12040894 ◽

2020 ◽

Vol 12 (4) ◽

pp. 894 ◽

Cited By ~ 3

Author(s):

Jared A. Cohen ◽

Riccardo Bomben ◽

Federico Pozzo ◽

Erika Tissino ◽

Andrea Härzschel ◽

...

Keyword(s):

Targeted Therapy ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Predictive Biomarkers ◽

Variable Region ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Region Gene ◽

Novel Biomarkers

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

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