scholarly journals Prognostic significance of aberrant CD5 expression in B-cell leukemia

2019 ◽  
Vol 13 (1) ◽  
Author(s):  
Kaveh Jaseb ◽  
Daryush Purrahman ◽  
Saeid Shahrabi ◽  
Majid Ghanavat ◽  
Hadi Rezaeean ◽  
...  
Keyword(s):  
B Cell ◽  
English Language ◽  
Clinical Course ◽  
Relevant Literature ◽  
Prognostic Significance ◽  
Cell Leukemia ◽  
B Cell Malignancies ◽  
Aberrant Expression ◽  
B Cell Leukemia ◽  
Prognostic Importance

Aberrant expression of CD5 (as a T-cell marker) is seen in some leukemia and lymphoma of B lineage origin. Given that the signaling resulting from the expression of this marker plays an essential role in the development of leukemia and lymphoma, evaluating the expression of this marker is of paramount importance. Therefore, our goal in this study was to investigate the prognostic importance of CD5 expression in B-cell leukemia and lymphoma. We evaluate CD5 expression in normal and leukemic B-cells by identifying relevant literature through a PubMed search (1998-2018) of English language papers using the terms: ‘CD5,’ ‘B-cell,’ ‘Leukemia,’ and ‘Lymphoma.’ We are doing this thorough comparison of results from CD5 positive and negative cases to make a correct decision about prognostic importance of CD5 expression in these malignancies. In a number of B-cell malignancies, CD5 is expressed in varying degrees. Due to the different origins and characteristics of these malignancies, the results of CD5 expression evaluations are heterogeneous and impossible to generalize. However, CD5 expression is sometimes associated with clinicopathologic findings, more invasive clinical course, and even resistance to treatment (specifically in DLBCL) among CD5- positive patients, which appears to be a function of CD5 signaling and its downstream factors such as STAT3. Depending on the type of malignancy, CD5 expression is associated with good or bad prognosis, which can be used as an auxiliary prognostic factor to assess the clinical course of B-cell malignancies. Moreover, the difference in expression levels of CD5 in a variety of B-cell malignancies allows for differential diagnosis of these malignancies, which can be helpful when diagnosis is difficult.

scholarly journals BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

2017 ◽  
Vol 1 (24) ◽  
pp. 2147-2160 ◽  
Author(s):  
Yo-Ting Tsai ◽  
Aparna Lakshmanan ◽  
Amy Lehman ◽  
Bonnie K. Harrington ◽  
Fabienne McClanahan Lucas ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Disease Progression ◽  
Immune Suppression ◽  
Immune Modulation ◽  
Cell Leukemia ◽  
B Cell Malignancies ◽  
New Model ◽  
Key Points ◽  
B Cell Leukemia

Key PointsMutated BRAF accelerates disease and enhances immune abnormalities in murine B-cell leukemia. This new model will be valuable for understanding and targeting disease-induced immune modulation in MAPK-mutated B-cell malignancies.

BMI1, the Polycomb-Group Gene, Is Recurrently Targeted by Genomic Rearrangements in Progressive B-Cell Leukemia/Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1099-1099
Author(s):  
Leila Rouhi ◽  
Natalie Put ◽  
Thomas Tousseyn ◽  
Julio Finalet Ferreiro ◽  
Wim De Kelver ◽  
...  
Keyword(s):  
Stem Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Polycomb Group ◽  
Prognostic Impact ◽  
Cell Leukemia ◽  
Genomic Amplification ◽  
Aberrant Expression ◽  
B Cell Leukemia ◽  
Vh Genes

Abstract Abstract 1099 Poster Board I-121 The 10p11 chromosomal site is recurrently affected by genomic abnormalities in B cell leukemia/lymphoma, but the molecular consequences of these aberrations remain unknown. We have collected three cases (2 female, 1 male; 67-69 years) of chronic lymphocytic leukemia (CLL) with a novel IGH-mediated t(10;14)(p11;q32) (#1 and 2) or its IGL variant t(10;22)(p11;q11) (#3), and one case of blastic mantle cell lymphoma (MCL) with a complex t(11;14)-positive karyotype including add(10)(p12) (#4). Case 1 showed unmutated VH genes and usage of VH3-21/D1-26/JH6. Cases 2 and 3 revealed mutated VH genes and usage of VH3-21/D1-14/JH4 and VH3-11/D4-4/JH6, respectively. In cases 1 and 2 with a monoallelic loss of RB1, the t(10;14)(p11,q32) was found as a secondary change at time of CLL progression/Richter transformation observed 148 and 50 months after diagnosis, respectively. In case 3, the sole t(10;22)(p11;q11) was identified at time of CLL diagnosis. All three patients died from disease progression 37-149 months after diagnosis. Of note, both patients with t(10;14) died from refractory disease 1 and 3 months after CLL progression/transformation and genetic detection f t(10;14). The patient #3 did not require therapy, but died from septic shock 37 months after diagnosis, and autopsy revealed diffuse and massive lymph node and spleen involvement. The patient with MCL (#4), 67 years old man with a previous history of prostatic adenocarcinoma and CLL, developed secondary central nervous system liesions and died 40 months after diagnosis of MCL. Extensive FISH studies of t(10;14) and t(10;22) mapped the 10p11 breakpoint in the region of the BMI1 locus. SNP array analysis of case 4 complemented by FISH identified amplification of the 10p11 region covering BMI1. Immunostaining with anti-BMI1 serum performed in 2 available cases (#2 and 3) showed expression of the BMI1 protein by neoplastic cells. This approach, however, did not allow to estimate whether the level of BMI1 expression in these cases was higher than in control CLL cases. BMI1 (B-cell-specific Moloney murine leukemia virus integration site 1) is a member of the Polycomb group of genes that are important epigenetic chromatin modifiers with an essential role in embryogenesis and the maintenance of adult stem cells. BMI1 was first identified as a protooncogene that cooperates with c-myc in the generation and development of mouse pre B-cell lymphomas. The BMI1 protein is a component of Polycomb repressive complex1 (PRC1), one of two multiprotein PRCs that maintain cell identity by gene suppression. The gene plays an important role in self-renewal of hematopoietic and neural stem cells. Multiple lines of evidence implicate BMI1 and other Polycomb genes in tumorigenesis. Among others, an aberrant expression of BMI1 has been observed in a wide spectrum of cancers and usually correlated with unfavourable clinical outcome. BMI1 is one of the genes marking the ABC-type signature of DLBCL, associated with a poor prognosis. High levels of BMI1 mRNA/protein were also detected in CLL, MCL, MM and HL. In some MCLs, overexpression of BMI1 correlated with genomic amplification of the BMI1 gene detected by aCGH in 12-24% of analysed cases (Jares and Campo, 2008). BMI1 has been shown to contribute to cell cycle regulation and senescence by acting as transcriptional repressor of the INK4a-ARF tumor suppressors. Despite the wealthy information on BMI1 contributing to a variety of tumors, molecular mechanisms underlying deregulation of BMI1 in neoplasms and functional consequences of these events remain elusive. In summary, we show for the first time that BMI1, a postulated lymphoma-related oncogene, is recurrently targeted by IG-mediated chromosomal translocations in CLL and confirm its amplification in MCL. We found that in both cases with t(10;14)/IGH-BMI1, the translocation was acquired during clinical transformation of CLL initially harboring the del(13q)/RB1. The adverse prognostic impact of BMI1 aberrations in all four collected cases is reflected by a constantly aggressive clinical course of disease and short survival of the affected patients (1-50 months). In this regard, further molecular studies of the BMI1 pathway and its downstream partners are necessary to develop novel therapeutic approaches targeting this oncogene in human cancers. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 776-776
Author(s):  
Jae-Woong Lee ◽  
Kohei Kume ◽  
Zhengshan Chen ◽  
Gang Xiao ◽  
Kadriye Nehir Cosgun ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Receptor ◽  
Transplant Recipients ◽  
Cell Leukemia ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
Receptor Chain ◽  
B Cell Leukemia ◽  
Cancer Types

Abstract Studying gene expression and clinical outcome data from 136 clinical trials for patients with cancer (~21,000 patients with 26 cancer types), we found CD25 as one of the strongest predictors of poor clinical outcome in patients with B-cell malignancies, but not in other cancer types. This was unexpected because CD25 is known as one of three chains of the IL2 receptor on T-cells and NK-cells. Interleukin-2 (IL2) functions as essential T-cell growth factor. IL2 signals through β- and γ-, but not α-chains (CD25) of its heterotrimeric receptor. CD25-deficiency causes lymphoproliferation and autoimmunity, however, its mechanistic role is unclear. Our experiments based on genetic mouse models and engineered patient-derived B-cell leukemia and lymphoma xenografts revealed that CD25 expressed on B-cells is not an IL2 receptor chain, but in fact binds the B-cell receptor (BCR) to regulate its activity. Suggesting IL2-independent functions, defects in CD25-/-B-cells were not replicated in IL2-deficient mice. CD25 bound the BCR but not IL2Rβ- and IL2Rγ-chains. IL2Rβ- and IL2Rγ-chains can pair with other chains to form receptors for different cytokine-ligands. However, CD25 represents the first example of a cytokine receptor chain that binds to the BCR for negative feedback regulation. Likewise, in T-cells, CD25 had a bifunctional role and either functioned as IL2 receptor chain or as negative feedback regulator of T-cell receptor signaling. CD25-function was regulated by cell-membrane translocation, which required phosphorylation of its cytoplasmic tail at S268 (see schematic, left). In a family with monogenic autoimmunity, a mutation immediately preceding S268 compromised CD25-surface translocation, which was restored by homology-directed repair of the S268 motif. CD25-interactome analyses identified PKCd as critical effector molecule downstream of CD25 to mediate B-cell selection during normal B-cell development and calibrate oncogenic BCR signaling in B-cell tumors. In B-cell malignancies, BCR-dependent survival and proliferation signals are often substituted by oncogenic BCR-mimics (e.g. BCR-ABL1, JAK2, BRAFV600E, LMP2A, CD79B mutations; see schematic, right). Accordingly, we identified CD25 surface-expression as biomarker of oncogenic BCR-signaling and predictor of poor clinical outcomes. CD25-/-B-cell leukemia failed to initiate fatal disease in transplant recipients. Owing to imbalances of oncogenic BCR-signaling and p53-checkpoint activation, CD25-/- B-cell leukemia failed to initiate fatal disease in transplant recipients. In patient-derived xenograft models of drug-resistant B-cell malignancies, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extended survival of transplant recipients or eradicated disease. These findings identified CD25 as previously unrecognized feedback regulator of oncogenic BCR-signaling and provide a rationale for therapeutic targeting of CD25 in refractory B-cell malignancies. Figure. Figure. Disclosures Forman: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Weinstock:Genentech/Roche, Monsanto: Consultancy; Novartis: Consultancy, Research Funding; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties. Uzel:Novartis: Research Funding.

scholarly journals Dynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 393-393
Author(s):  
Jaewoong Lee ◽  
Kohei Kume ◽  
Zhengshan Chen ◽  
Gang Xiao ◽  
Kadriye Nehir Nehir Cosgun ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Cytoplasmic Tail ◽  
Cell Receptor ◽  
Transplant Recipients ◽  
Cell Leukemia ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
B Cell Leukemia

Background: Studying gene expression and clinical outcome data from 136 clinical trials for patients with cancer (~21,000 patients with 26 cancer types), we found CD25 as one of the strongest predictors of poor clinical outcome in patients with B-cell malignancies, but not in other cancer types. This was unexpected because CD25 is known as one of three chains of the IL2 receptor on T-cells and NK-cells. Interleukin-2 (IL2) functions as essential T-cell growth factor. IL2 signals through b- and g-, but not a-chains (CD25) of its heterotrimeric receptor. CD25-deficiency causes lymphoproliferation and autoimmunity, however, its mechanistic role is unclear. Results: Our experiments based on genetic mouse models and engineered patient-derived B-cell leukemia and lymphoma xenografts revealed that CD25 expressed on B-cells is not an IL2 receptor chain, but in fact binds downstream signaling molecules of the B-cell receptor (BCR). Through these interactions, CD25 mediates negative feedback to BCR signaling in response to antigen-encounter in normal B-cells. Defects in CD25-/-B-cells were not replicated in mice that express CD25 but lack expression of the IL2 cytokine. These findings demonstrate IL2-independent functions of CD25 in B-cells and B-cell derived leukemia and lymphoma. To comprehensively study the interactome of the short cytoplasmic tail of CD25, we performed proximity-dependent biotin identification (BioID). This analysis revealed that the CD25 tail exerts negative feedback control through recruitment of the PKCβ-scaffold RACK1 and the inhibitory phosphatase SHIP1 (see schematic, left). Interestingly, the cytoplasmic tail of CD25 harbors a PKCβ-substrate motif and mutation of a central serine residue (S268) to A268 compromised interactions with PKCβ, its scaffold RACK1 and SHIP1, demonstrating that feedback control was dependent on PKCβ-mediated phosphorylation of CD25-S268. A genetic observation in a family with monogenic autoimmunity confirmed the functional importance of the cytoplasmic CD25-tail motif: a mutation immediately preceding S268 compromised CD25-surface translocation, which was restored by homology-directed repair of the S268. In vitro kinase assay with 62 candidate kinases against recombinant cytoplasmic tail of CD25-S268 or -A268 identified PKCβ as top-ranking kinase hit for CD25-S268 but not CD25-A268. Our genetic studies revealed that PKCβ is required for cell-membrane translocation of CD25, but also transcriptional expression of CD25 via NF-κB activation. Therefore, PKCβ act as critical effector molecule downstream of CD25 to mediate B-cell selection during normal B-cell development and calibrate oncogenic BCR signaling in B-cell tumors. In B-cell malignancies, BCR-dependent survival and proliferation signals are often substituted by oncogenic BCR-mimics (e.g. BCR-ABL1, JAK2, BRAFV600E, LMP2A, CD79B mutations; see schematic, right). Accordingly, we identified CD25 surface-expression as biomarker of oncogenic BCR-signaling and predictor of poor clinical outcomes. CD25-/-B-cell leukemia failed to initiate fatal disease in transplant recipients. Owing to imbalances of oncogenic BCR-signaling and p53-checkpoint activation, CD25-/- B-cell leukemia failed to initiate fatal disease in transplant recipients. In patient-derived xenograft models of drug-resistant B-cell malignancies, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extended survival of transplant recipients or eradicated disease. These findings identified CD25 as previously unrecognized feedback regulator of oncogenic BCR-signaling and provide a rationale for therapeutic targeting of CD25 in refractory B-cell malignancies. Figure Disclosures Zammarchi: ADC Therapeutics: Employment. Van Berkel:ADC Therapeutics: Research Funding. Melnick:Constellation: Consultancy; Janssen: Research Funding; Epizyme: Consultancy. Luger:Celgene: Research Funding; Cyslacel: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Kura: Research Funding; Onconova: Research Funding; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria. Meffre:AbbVie: Consultancy, Other: Grant. Weinstock:Celgene: Research Funding.

Prognostic significance of pre B cell leukemia transcription factor 2 (PBX2) expression in non-small cell lung carcinoma

2009 ◽  
Vol 100 (7) ◽  
pp. 1198-1209 ◽  
Author(s):  
Ying Qiu ◽  
Eiichi Morii ◽  
Yasuhiko Tomita ◽  
Binglin Zhang ◽  
Akihide Matsumura ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Prognostic Significance ◽  
Small Cell ◽  
Cell Leukemia ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
B Cell Leukemia

Hepatic B cell leukemia-3 attenuates chemically-induced hepatocarcinogenesis in mice

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
N Gehrke ◽  
MA Wörns ◽  
Y Alt ◽  
A Waisman ◽  
N Hoevelmeyer ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Leukemia ◽  
Chemically Induced ◽  
B Cell Leukemia

A clinical and histologic mycosis fungoides simulant occurring as a T-cell infiltrate coexisting with B-cell leukemia cutis

1995 ◽  
Vol 33 (2) ◽  
pp. 341-345 ◽  
Author(s):  
Michael S Metzman ◽  
Seth R Stevens ◽  
Christopher E.M Griffiths ◽  
Charles W Ross ◽  
Jay M Barnett ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mycosis Fungoides ◽  
Cell Leukemia ◽  
Cell Infiltrate ◽  
B Cell Leukemia ◽  
Leukemia Cutis
Sign in / Sign up

Export Citation Format

Share Document