scholarly journals The microenvironment in mature B-cell malignancies: a target for new treatment strategies

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3367-3375 ◽  
Author(s):  
Jan A. Burger ◽  
Paolo Ghia ◽  
Andreas Rosenwald ◽  
Federico Caligaris-Cappio
Keyword(s):  
B Cell ◽  
Residual Disease ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
B Cell Malignancies ◽  
Accessory Cells ◽  
Specialized Tissue ◽  
New Treatment ◽  
Novel Strategy ◽  
Secondary Lymphoid Organs

AbstractDespite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.

Endometrial Cancer State of the Science Meeting

2009 ◽  
Vol 19 (1) ◽  
pp. 134-140 ◽  
Author(s):  
Henry C. Kitchener ◽  
Edward L. Trimble
Keyword(s):  
Endometrial Cancer ◽  
Current Knowledge ◽  
Gynecological Cancer ◽  
Treatment Strategies ◽  
List Type ◽  
Uterine Carcinosarcoma ◽  
National Cancer Research Institute ◽  
Key Issues ◽  
New Treatment ◽  
State Of The Science

There is a pressing need to improve our understanding of endometrial cancer (EC) and uterine carcinosarcoma and to develop new treatment strategies to improve outcomes. In recognition of this, a State of the Science meeting on EC was held last November 28 and 29, 2006, in Manchester, United Kingdom. The meeting was cosponsored by the National Cancer Research Institute (UK), the National Cancer Institute (US), and the Gynecological Cancer Intergroup.The objectives of the meeting were as follows: To review current knowledge and understanding of EC and its treatments.To identify key issues for translational research and clinical trials.To identify the most important trials for women with endometrial carcinoma and uterine carcinosarcoma, both those already underway or to be done, for which the Gynecological Cancer Intergroup might facilitate international cooperation.

All Clones Are Not Equal: Somatic Hypermutation Significantly Enhances The Utility Of Tumor Tagging Rearrangements At IG Light Chain Loci In B Cell Malignancy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1376-1376
Author(s):  
Christopher S Carlson ◽  
Bryan Howie ◽  
Alfred L. Garfall ◽  
Eline Luning Prak
Keyword(s):  
B Cells ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Light Chain ◽  
False Positive ◽  
Residual Disease ◽  
B Cell Malignancies ◽  
Tumor Tracking ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Select tumor tag sequences, informed by the probability of generating the same sequence in an independent recombination event, are likely to be useful in tracking mature B cell malignancies where the IGH locus has been deleted. We considered the use of IGK and IGL for this purpose, but found that 2-4% of these rearrangements were shared between different individuals. The relatively high frequencies of such public rearrangements at IGK and IGL prompted us to search for other forms of sequence diversity that could be used as private clonotypic tags. Somatic hypermutations (SHM) may serve such a function. Our analysis of IGK and IGL suggests that tumor tracking sequences for detecting minimal residual disease should be selected with care, and these loci may be best suited for lymphoid malignancies that are characterized by high levels of SHM. Tracking minimal residual disease for B cell malignancies is an established technology, traditionally using either flow cytometry or a custom quantitative PCR assay for each patient. Recent technical developments in the massively parallel sequencing of somatically rearranged IG loci allow for a standard assay to be applied to screen for residual tumor burden in all patients, by first identifying the clonal IG rearrangements tagging the tumor in an index sample taken from the patient during active disease, and then screening for these tumor tagging sequences in follow up samples. A crucial assumption in these tagging strategies is that the tumor tagging sequences are idiosyncratic to the tumor, and unlikely to be generated independently in a recurrent rearrangement. In order to screen for recurrent sequences between two healthy individuals, we generated IG heavy and light chain libraries from 100,000 antigen experienced B cells (CD19+CD27+) isolated from whole blood by FACS. 130 bp reads were collected, starting within the J segment and extending across the CDR3 into the V segment. Unique sequences were compared between individuals to assess the frequency of nucleotide identical, “public” rearrangements shared between individuals. Less than 0.01% of unique IGH sequences overlapped between individuals, so the risk of a false positive MRD result from recurrent recombination at IGH is minimal. However, 4.3% and 1.9% of unique sequences at IGK and IGL, respectively, were shared between individuals. The shared sequences had significantly higher average copy numbers than unshared sequences, accounting for 20% of total sequences at IGK and 12% of total sequences at IGL. These data suggest that B cells carrying public sequences undergo higher levels of clonal expansion, and/or they are recurrently produced. Public sequences carried by B cell malignancies are likely to be of limited utility as tumor-tagging sequences, as it may be impossible to distinguish between low-level residual disease and benign, recurrent rearrangements in the patient. Therefore we assessed if we could predict whether a given sequence in the memory repertoire would be public using solely information derived from that sequence. We used logistic regression to screen for variables to predict the likelihood of a given sequence to be public, and identified a number of expected variables as significant predictors, including the identity of the V and J segments, the length of the non-templated insertion at the junction, and the number of somatic hypermutations within the V or J segment. By far the most important of these factors was the number of SHM events in the clone; consequently, the most useful light chains for tumor tracking will be those with significant SHM. We continue to explore factors contributing to the public IG repertoire. Particularly at IGK, there is an unexpectedly narrow range of CDR3 lengths, and we are determining if this might be attributable to low diversity in the primary repertoire, or due to positive selection in favor of this length in the mature naïve or mature repertoires. In conclusion, a high frequency of public IG light chain sequences in the antigen- experienced peripheral B cell repertoire suggests that naïve application of light chain clones for tracking MRD can generate false positive results, but that careful selection of tumor tracking sequences with SHMs can minimize this risk. Disclosures: Carlson: Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Howie:Adaptive Biotechnologies: Employment, Equity Ownership.

a Novel Method for the Detection of Minimal Residual Disease in B-Cell Malignancies: Ion Semiconductor Sequencing for the Evaluation of Igh Gene Rearrangements

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2983-2983
Author(s):  
Silvia Gimondi ◽  
Alessandra Cavanè ◽  
Antonio Vendramin ◽  
Giulia Biancon ◽  
Paolo Corradini ◽  
...  
Keyword(s):  
B Cell ◽  
Multiplex Pcr ◽  
Residual Disease ◽  
Chain Reaction ◽  
B Cell Malignancies ◽  
Specific Primers ◽  
Namalwa Cell ◽  
Polymerase Chain ◽  
Minimal Residual

Abstract Background: Minimal residual disease (MRD) detection is of high clinical relevance in patients with B-cell malignancies and is generally a surrogate parameter to evaluate treatment response and long-term prognosis. IgH gene rearrangements can be used as molecular marker in approximately 80% of lymphoma and myeloma patients since they represent lineage-specific markers and the complementarity determining region 3 (CDR3) is unique to each clone. To date, allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and real-time quantitative polymerase chain reaction (RQ-PCR) are considered the most sensitive and widely applicable methods for MRD detection. A major disadvantage of ASO-PCR and RQ-PCR assays, is the use of specific primers and probes for every individual patient. Clone-specific primers and probes are not only expensive but also time-consuming to design and to test, which limits their wide applicability in the clinical setting. The recent major improvements in next generation sequencing (NGS) technologies, provide the opportunity to identify and quantify clonotypes with consensus primers combining the benefits of high sensitivity and universal applicability. The present work was designed to overcome ASO-PCR and RQ-PCR limitations by developing a feasible method for rearranged IgH genes amplification, NGS and analysis using Ion Torrent Personal Genome Machine (IT-PGM). Methods: To define a multiplex PCR protocol, DNA from 7 CLL patients, previously shown to bare a family specific clonal VDJ rearrangement, was amplified with a pool of the seven different family-specific IgH-V primers, and a consensus JH primer (Voena et al., Leukemia 1997). After Sanger sequencing, results were compared to the ones obtained with singleplex PCR protocol. Once validated, the multiplex PCR protocol was used to amplify DNA from patients and serially diluted (up to 10-8 ) DNA from Namalwa cell line (bearing a known IgH rearrangement) and subsequently sequenced on the IT-PGM using the 316 Ion-chip. NGS data were analyzed by using the IMGT-High V-Quest web server tool and the statistical software R. RQ-PCR was used to quantify the specific VDJ rearrangement in the serially diluted Namalwa DNA solutions and in DNA from patients as previously described (Farina et al, Haematologica 2009). RQ-PCR data were analyzed through a relative quantification procedure. Results: The multiplex PCR reactions we have tested, demonstrated the same specificity as the standard singleplex PCR protocol and therefore was used to construct the DNA library required for IT-PGM-based sequencing. The IT-PGM sequencing output is represented by at least 400000 reads per sample with a minimum average coverage of the VDJ repertoire of 500x. The IMGT-High V-quest tool allows a user-friendly web based analysis and a deep molecular characterization of the IgH recombinatorial repertoire. Namalwa clonal CRD3 sequences were detected up to a dilution of 10-5 without the need for specific CDR3 primers. Comparability of NGS and ASO RQ-PCR results was assessed. The use of CDR3 specific primers, along with the specific IgH-V family fluorescent probe, enabled the identification of clonal VDJ rearrangements with a sensitivity up to 10-5 (2/3 replicates) and 10-6 (just 1/3 replicates) in Namalwa Cell Line. Similar results were obtained when we characterized the IgH recombination repertoire of two CLL patients over time. Conclusions: IgH sequencing with the IT-PGM platform showed at least the same level of sensitivity as ASO RQ-PCR, without the need for patient-specific reagents. It also allows specific and detailed molecular characterization of the clonal rearrangements and could be easily incorporated into clinical laboratories for routine testing of MRD in B-cell malignancies. Disclosures No relevant conflicts of interest to declare.

Immunoglobulin heavy-chain consensus probes for real-time PCR quantification of residual disease in acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2651-2658 ◽  
Author(s):  
John W. Donovan ◽  
Marco Ladetto ◽  
Guangyong Zou ◽  
Donna Neuberg ◽  
Christina Poor ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Cell ◽  
B Cell ◽  
Heavy Chain ◽  
Real Time Pcr ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
B Cell Malignancies ◽  
Normal Cells ◽  
Pcr Method

Tumor-related immunoglobulin heavy-chain (IgH) rearrangements are markers for polymerase chain reaction (PCR) detection of minimal residual disease (MRD) in B-cell malignancies. Nested PCR with patient IgH allele-specific oligonucleotide primers can detect 1 tumor cell in 104 to 106 normal cells. In childhood acute lymphoblastic leukemia (ALL), persistence of PCR-detectable disease is associated with increased risk of relapse. The clinical significance of qualitative PCR data can be limited, however, because patients can harbor detectable MRD for prolonged periods without relapse. Recent studies indicate that a quantitative rise in tumor burden identifies patients who are at high risk for relapse. Therefore, an efficient and reliable PCR method for MRD quantification is needed for ALL patients. We have developed a real-time PCR method to quantify MRD with IgH VH gene family consensus fluorogenically labeled probes. With this method, a small number of probes can be used to quantify MRD in a large number of different patients. The assay was found to be both accurate and reproducible over a wide range and capable of detecting approximately 1 tumor cell in 5 × 104 normal cells. We demonstrate that this methodology can discriminate between patients with persistence of MRD who relapse and those who do not. This technique is generally applicable to B-cell malignancies and is currently being used to quantify MRD in a number of prospective clinical studies at our institution.

Can opportunistic case-finding of paraproteins be clinically justified?

2005 ◽  
Vol 42 (4) ◽  
pp. 245-253 ◽  
Author(s):  
Robert Beetham ◽  
Neil Howie ◽  
Richard Soutar
Keyword(s):  
B Cell ◽  
Ethical Issues ◽  
Current Knowledge ◽  
Laboratory Data ◽  
Outcome Data ◽  
B Cell Malignancies ◽  
Laboratory Staff ◽  
The Uk ◽  
Initial Objective ◽  
Do So

The addition of serum protein electrophoresis by laboratory staff upon finding an increased total protein or globulin appears to be practised widely in the UK. The criteria for assessing which samples are subject to electrophoresis vary considerably. They consist of initial objective laboratory data subsequently modified, somewhat subjectively, by other laboratory data and clinical details, but have often been chosen pragmatically. The aim of the practice is to identify patients with occult B-cell malignancies that warrant treatment. While it has been lent legitimacy in many cases by involving clinical haematologists in discussions, the views of other stakeholders, including other physicians and patients, have often not been considered, thus raising a number of ethical questions that need to be addressed. The practice is reviewed against both current knowledge of B-cell malignancies and monoclonal gammopathy of undetermined significance and criteria for screening, of which this forms a particular example. The arguments for and against addition of electrophoresis are finely balanced, partly because of the very limited outcome data available. We conclude that those currently following this practice should continue to do so, there is a need to establish outcome data as widely as possible according to standard criteria and there should be involvement of physicians, patients and national bodies in discussions about the practice so that the practical and ethical issues can be addressed.

scholarly journals Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

2021 ◽  
Author(s):  
Joanna Ewa Sowa ◽  
Krzysztof Tokarski
Keyword(s):  
Glial Cells ◽  
Network Effects ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Neurological Impairment ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Biased Signaling ◽  
New Treatment

AbstractAccumulating evidence highlights chemokines as key mediators of the bidirectional crosstalk between neurons and glial cells aimed at preserving brain functioning. The multifaceted role of these immune proteins in the CNS is mirrored by the complexity of the mechanisms underlying its biological function, including biased signaling. Neurons, only in concert with glial cells, are essential players in the modulation of brain homeostatic functions. Yet, attempts to dissect these complex multilevel mechanisms underlying coordination are still lacking. Therefore, the purpose of this review is to summarize the current knowledge about mechanisms underlying chemokine regulation of neuron–glia crosstalk linking molecular, cellular, network, and behavioral levels. Following a brief description of molecular mechanisms by which chemokines interact with their receptors and then summarizing cellular patterns of chemokine expression in the CNS, we next delve into the sequence and mechanisms of chemokine-regulated neuron–glia communication in the context of neuroprotection. We then define the interactions with other neurotransmitters, neuromodulators, and gliotransmitters. Finally, we describe their fine-tuning on the network level and the behavioral relevance of their modulation. We believe that a better understanding of the sequence and nature of events that drive neuro-glial communication holds promise for the development of new treatment strategies that could, in a context- and time-dependent manner, modulate the action of specific chemokines to promote brain repair and reduce the neurological impairment.

Characteristics of the Immunoglobulin Heavy Chain (IgH) Rearrangement in Multiple Myeloma (MM): An Analysis On 308 Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2808-2808
Author(s):  
Simone Ferrero ◽  
Daniela Capello ◽  
Mirija Svaldi ◽  
Michela Boi ◽  
Daniela Drandi ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Somatic Hypermutation ◽  
Current Knowledge ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Major Step ◽  
Cell Repertoire ◽  
Igh Rearrangement

Abstract Abstract 2808 Poster Board II-784 Background and aims: Characterization of the IgH receptor provides useful insights to understand the pathogenesis and natural history of lymphoid tumors. For example the recognition of stereotyped clusters of immunoglobulin receptors has been a major step forward to understand the pathogenesis of chronic lymphocytic leukemia (CLL). IgH rearrangements have been less extensively investigated in MM, mostly because of lack of large databases of IgH sequences. At our Institution a large number of MM patients has undergone IgH sequencing for minimal residual disease (MRD) evaluation. This database has been merged with MM IgH sequences available in the literature, resulting in 308 MM sequences which have been employed to comprehensively investigate the characteristics of the IgH rearrangement in this tumor. Patients and methods: 131 IgH genes from MM patients were amplified and direct sequenced at our Institution (mostly for MRD detection purposes) from specific cDNA obtained at diagnosis, as already described (Voena et al, Leukemia 1997). 177 MM IgH sequences were derived from published databases (NCBI and EMBL). To further characterize the IgH repertoire, we have then compared the MM complementarity-determining region 3 (HCDR3) amino acid (AA) sequences to a panel of productive, non redundant 27413 HCDR3 AA sequences retrieved from public databases (EMBL, NCBI, IMGT/LIGM-DB: 25655 sequences) and from our unpublished laboratory database (1758 sequences), including sequences from malignant B-cell clones (3197 CLL, 1217 lymphomas) and from non malignant repertoire (2685 autoreactive, 4408 immunederegulation/immunodeficiency, 15429 normal and 477 phage display libraries). All the sequences have been analyzed using the IMGT database and tools (Lefranc et al., Nucleic Acid Res. 2005; http://imgt.cines.fr/) to identify IGHV, IGHD and IGHJ gene usage, to assess the somatic hypermutation (SHM) rate and to identify HCDR3 AA sequences. HCDR3 AA sequences were aligned together, in search of subsets of stereotyped receptors, using the ClustalX 2.0 software (http://www.clustal.org/). To define subsets of stereotyped IgH receptors, we followed the criteria proposed by Messmer et al. (J Exp Med. 2004) and Stamatopoulos et al. (Blood, 2007). Results: No significant differences were noted between our Institutional and published MM databases. Overall IGHV usage in MM appeared in keeping with the normal B cell repertoire with predominance of IGHV3 family (53.9%) followed by IGHV4 (slightly under-represented in MM, 17.2% vs 23.2%, p=0.02) and IGHV1 (12%); besides an over-representation of IGHV2 (7.8% vs 2.3%, p<0.001) was noticed. A modest but significant (p<0.05) over-representation of the IGHV3-9 (5.2% vs 2.6%), IGHV3-21 (4.5% vs 2%), IGHV5-51 (4.5% vs 2.2%) genes and under-representation of the IGHV3-23 (8.1% vs 12.2%) and IGHV4-34 (1% vs 6.5%, p<0.001) were observed. IGHD and IGHJ followed a distribution similar to that of normal IgH repertoire. The median SHM rate was 7.5% (range 0-28%): interestingly we found one single patient with 100% identity to the germline sequence and only three patients with >98% identity. The median length of the HCDR3 was 15 AA (range 7-29), again in line with normal IgH repertoire. Intra MM search for HCDR3 similarity showed no association which met minimal requirements to define stereotyped receptors. The comparison of MM sequences with non MM database showed that 98% of MM sequences are unrelated to known CLL subsets. Among the remaining, 3 MM sequences could be assigned to previously identified CLL subsets (namely n. 25, n. 37 and n. 71 according to Murray et al., Blood 2008) whereas 2 MM formed 2 novel provisional subsets with CLL. When HCDR3 MM were compared to the database of non MM/CLL HCDR3, similarities were found with clones from normal B cells, while similarities with autoreactive clones and other B cell malignancies were sporadic. Conclusions: The analysis of the largest database of MM IgH sequences so far reported indicate the following: 1) Family usage in the MM IgH repertoire follows a nearly physiological distribution apart for modest skewing of a number of IGHV genes; 2) MM specific HCDR3 clusters do not occur to a frequency detectable with currently available databases; 3) The vast majority of MM sequences are not related to known CLL clusters; 4) MM IgH sequences share more similarities with normal IgH sequences compared to those derived from pathological B lymphoid cells. Thus to state of current knowledge there is little evidence in favor of an antigen driven pathogenesis for this neoplasm. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clostridioides difficile Phage Biology and Application

2021 ◽  
Author(s):  
Joshua Heuler ◽  
Louis-Charles Fortier ◽  
Xingmin Sun
Keyword(s):  
Phage Therapy ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Bacterial Gene ◽  
Healthcare Settings ◽  
Bacterial Gene Expression ◽  
Clostridioides Difficile ◽  
New Treatment ◽  
Further Development ◽  
Insight Into

Abstract Clostridium difficile, now reclassified as Clostridioides difficile, is the causative agent of C. difficile infections (CDI). CDI is particularly challenging in healthcare settings because highly resistant spores of the bacterium can persist in the environment, making it difficult to curb outbreaks. Dysbiosis of the microbiota caused by the use of antibiotics is the primary factor that allows C. difficile to colonize the gut and cause diarrhea and colitis. For this reason, antibiotics targeting C. difficile can be ineffective at preventing recurrent episodes because they exacerbate and prolong dysbiosis. The emergence of antibiotic resistance in C. difficile also presents a significant threat. The diverse array of bacteriophages (phages) that infect C. difficile could offer new treatment strategies and greater insight into the biology of the pathogen. In this review, we summarize the current knowledge regarding C. difficile phages and discuss what is understood about their lifestyles and genomics. Then, we examine how phage infection modifies bacterial gene expression and pathogenicity. Finally, we discuss the potential clinical applications of C. difficile phages such as whole phage therapy and phage-derived products, and we highlight the most promising strategies for further development.

scholarly journals Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1587-1587
Author(s):  
Zhengshan Chen ◽  
Markus Muschen
Keyword(s):  
Drug Resistance ◽  
B Cells ◽  
B Cell ◽  
Negative Selection ◽  
Cell Types ◽  
Oncogenic Signaling ◽  
B Cell Malignancies ◽  
Minimum Threshold ◽  
Bcr Signaling ◽  
Novel Strategy

Abstract Concept. Targeted therapy of cancer typically focuses on inhibitors (e.g. tyrosine kinase inhibitors) that suppress oncogenic signaling below a minimum threshold required for survival and proliferation of cancer cells. Acute lymphoblastic leukemia (ALL) and B cell lymphomas originate from various stages of development of B cells, which unlike other cell types are under intense selective pressure. The vast majority of newly generated B cells are autoreactive and die by negative selection at autoimmunity checkpoints (AIC). Owing to ubiquitous encounter of self-antigen, autoreactive B cells are eliminated by overwhelming signaling strength of their autoreactive B cell antigen receptor (BCR). A series of recent findings suggests that, despite malignant transformation, AIC are fully functional in B cell malignancies. We propose that targeted engagement of AIC represents a previously unrecognized therapeutic opportunity to overcome conventional mechanisms of drug-resistance in pre-B ALL and other B cell malignancies. Results: Oncogenic drivers in B- cell malignancies function as mimics of B-cell receptor (BCR) signaling. Oncogenic activation of BCR-signaling represents the functional equivalent of positive selection during normal lymphocyte development. Addiction to survival and proliferation signals (or the equivalent of positive selection) is a common feature in many types of cancer. However, B-cell malignancies are unique in that they are also subject to an active negative selection process. B-cells expressing autoreactive BCRs or antibodies can cause systemic autoimmunity. As a safeguard against autoimmune diseases, lymphocyte development evolved autoimmunity checkpoints (AIC) to eliminate autoreactive clones. Owing to negative selection of autoreactive B-cells through AIC activation, lymphoid cells fundamentally differ in their signaling requirements from other cell types. Recent studies from our group showed that despite malignant transformation, B-cell leukemia and lymphoma cells are fully sensitive to negative selection and AIC-activation resulting (Chen et al., Nature 2015; Shojaee et al., Nature Med 2016; Chan et al., Nature 2017; Xiao et al., Cell 2018). AIC-activation in various lymphoid malignancies is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (see Schematic below). Unlike other types of cancer, B-cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive BCR. Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant leukemia and lymphoma clones. Here, we propose a novel strategy to overcome drug-resistance in B-lymphoid malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive B-lymphocytes. We have recently discovered that targeted hyperactivation of SYK, PI3K and ERK in B cell malignancies represents the functional equivalent of an autoimmunity checkpoint (AIC) for elimination of autoreactive clones among normal B cells. B cell tumors are uniquely vulnerable to AIC activation, suggesting that targeted activation of this checkpoint represents a novel strategy to induce cell death in otherwise drug-resistant B cell malignancies. Conclusion: Normal B-cells are positively selected for BCR signaling of intermediate strength (moderate activation of SYK, PI3K and ERK). In the absence of a functional BCR, SYK, PI3K and ERK activity fall below a minimum threshold, resulting in death by neglect. Hyperactivation above maximum thresholds (e.g. autoreactive BCR) triggers negative selection and cell death via AIC-activation. Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold. Our results support a novel strategy to overcome drug-resistance in B-cell malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive cells. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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