April Chiu

Memorial Sloan-Kettering Cancer Center, New York City, New York, United States

Are you April Chiu?

Claim your profile

Publications (32)320.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited. Experimental Design: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling and gene set enrichment analysis. Results are analyzed in correlation with cell-of-origin, critical lymphoma biomarkers and genetic translocations. Results: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in de novo DLBCL patients. When DLBCL cases were stratified according to cell-of-origin or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression and adverse clinical features. Gene expression profiling demonstrated up-regulation of genes, which can potentiate function of STAT3. Gene set enrichment analysis showed the JAK-STAT pathway to be enriched in pSTAT3+ DLBCL. Conclusions: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with R-CHOP in developed Western countries. Experimental design A large cohort (n=732) of patients with DLBCL treated with R-CHOP chemotherapy are included from the multicenter Consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by fluorescent in situ hybridization and mutation analysis, genomic information by gene expression profiling (GEP) and gene set enrichment analysis (GSEA). Results Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3 and CD30 were more commonly expressed in EBV+ DLBCLs (P<.05). Significant differences in survival were not observed in patients with EBV-positive DLBCL versus EBV-negative DLBCL. CD30 co-expression appeared to confer inferior outcome although statistical significance was not achieved. GEP showed a unique expression signature in EBV-positive DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways. Conclusions The clinical characteristics of patients with EBV+ versus EBV-negative DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, when present, is associated with an adverse outcome.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53-genetically defined large cohort of de novo DLBCL patients treated with R-CHOP chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n=478), MDM2 gene amplification by fluorescence in situ hybridization (n=364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n=108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression does not predict for an adverse clinical outcome in patients with wild-type p53, but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. Presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance, and important for designing therapeutic strategies that target the MDM2-p53 interaction.
    Blood 08/2013; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes according to their gene-expression signatures. In this study, we assessed a cohort of 893 de novo DLBCL patients treated with R-CHOP therapy. We show that MYC/BCL2 protein co-expression occurred significantly more commonly in the ABC subtype. The ABC and GCB subtypes had similar prognoses in DLBCL with MYC/BCL2 co-expression as well as in DLBCL without MYC/BCL2 co-expression. Consistent with the notion that the prognostic difference between the two subtypes was attributable to MYC/BCL2 co-expression, the difference in gene-expression signatures between the two subtypes was dramatically diminished in the absence of MYC/BCL2 co-expression. Furthermore, DLBCL with MYC/BCL2 co-expression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 co-expression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. Furthermore, the data suggest that MYC/BCL2 co-expression, rather than cell of origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP therapy.
    Blood 02/2013; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in approximately 14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+) 79% vs CD30- 59%, P=.001) and progression-free survival (P=.003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene-expression profiling revealed the up-regulation of genes encoding negative regulators of NF-kB activation and lymphocyte survival, and down-regulation of those involving B-cell receptor signaling and B-cell proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene-expression signature and significant value of CD30 as a therapeutic target for Brentuximab vedotin in ongoing successful clinical trials, it would be appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.
    Blood 01/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab (R) immuno-chemotherapy era remains undefined. In this large cohort of DLBCL patients treated with R-CHOP, we show that those with TP53 mutations had worse overall and progression-free survival compared to those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP treated patients with either the germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing >50% cells expressing p53 protein was a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.
    Blood 09/2012; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after Rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. Design and Methods. We analyzed Bcl-2 protein expression, BCL2 and MYC genes abnormalities by interphase fluorescence in situ hybridization in 327 Rituximab-CHOP treated de novo patients. Results. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in the germinal center subtype. The prognostic relevance of isolated MYC rearrangements was weaker compared to BCL2, but probably limited by their rarity. Seven of 8 patients with double hit lymphoma were germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome compared to patients without BCL2 rearrangements (p=0.0002), and their outcome was similar to activated B-cell subtype patients (p=0.30), but not as bad as double hit lymphoma patients (p<0.0001). Bcl-2 protein overexpression was associated with inferior outcome in germinal center subtype patients, but multivariate analysis showed that this was dependent on BCL2 translocations. The gene expression profiling of patients with BCL2 rearrangements was unique, showing activation of pathways that were silent in the negative counterpart. Conclusions. BCL2 translocated germinal center subtype patients have worse prognosis after Rituximab-CHOP, irrespective of MYC status, but the presence of combined gene breaks significantly overcomes the prognostic relevance of isolated lesions.
    Haematologica 08/2012; · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion, and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40L. Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of CD40, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, activation, Ig gene remodeling, and differentiation signals by stimulating CLL cells through TACI, BAFF-R, and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by upregulating the expression of leukemic CD40L. Inhibition of TACI, BCMA, and BAFF-R expression on CLL cells; abrogation of CD40 expression in MVECs; or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL, and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma.
    The Journal of Immunology 05/2012; 188(12):6071-83. · 5.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2012; 26(9):2103-13. · 10.16 Impact Factor
  • April Chiu, Attilio Orazi
    [Show abstract] [Hide abstract]
    ABSTRACT: Mastocytosis represents a heterogeneous group of disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis is further divided into different subtypes according to the sites of involvement, laboratory findings, and degree of organ impairment. Cutaneous mastocytosis is diagnosed in the presence of skin involvement and absence of extracutaneous disease, and is most commonly seen in the pediatric population. Systemic mastocytosis, the disease form most commonly seen in adults, is characterized by the presence of multifocal, compact (dense) mast cell aggregates in the bone marrow or other extracutaneous organs. The mast cells may display atypical, often spindle-shape morphology and/or aberrant CD2 and/or CD25 expression. Elevation of serum tryptase and/or presence of KIT D816V mutation are other common findings. Systemic mastocytosis is further divided into different subtypes based on a combination of clinical features and laboratory findings. Recent studies have indicated that CD30 is frequently expressed in aggressive systemic mastocytosis and mast cell leukemia but infrequently in indolent systemic mastocytosis, and may be a useful marker for distinguishing these subtypes of systemic mastocytosis from one another. A group of related myeloid disorders, collectively termed myelomastocytic overlap syndromes, may pose diagnostic difficulty because of their significant clinical and pathologic overlap with systemic mastocytosis, and these will also be discussed in this review.
    Seminars in Diagnostic Pathology 02/2012; 29(1):19-30. · 1.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.
    Nature Immunology 12/2011; 13(2):170-80. · 26.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Contact-dependent communication between immune cells generates protection, but also facilitates viral spread. We found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type-1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients harboring Nef-deficient virions, our data suggest that HIV-1 exploits intercellular highways as a “Trojan horse” to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2011; 56:44. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Splenic hamartoma is a rare tumor-like lesion composed of structurally disorganized red pulp elements. It has been hypothesized that two other splenic lesions, cord capillary hemangioma and myoid angioendothelioma, may fall within the spectrum of splenic hamartoma, simply representing morphological variants. In this study, we compared the vascular and stromal composition of cord capillary hemangioma and myoid angioendothelioma with those of classical hamartoma. In addition, we assessed the clonal vs polyclonal nature of the lesions in nine female cases by performing clonality analysis for X-chromosome inactivation at the human androgen receptor locus (HUMARA) on laser-assisted microdissected samples. In 15 of 17 cases, increased reticulin and/or collagen content was observed. The classical hamartoma cases showed a vasculature predominantly composed of CD8+ CD31+ CD34- splenic sinuses, whereas cases of cord capillary hemangioma and myoid angioendothelioma contained many CD8- CD31+ CD34+ cord capillaries, but very little CD8+ vasculature. All cases lacked expression of D2-40 and Epstein Barr virus-encoded RNA. All cases showed a proliferation index of ≤5% by Ki-67. Cases of classical hamartoma lacked significant perisinusoidal expression of collagen IV and low-affinity nerve growth factor receptor. Both markers were variably expressed in the other lesions. Increased CD163-positive histiocytes were found in four cases (three cord capillary hemangiomas and one myoid angioendothelioma). HUMARA analysis was informative in all nine tested cases, of which three cases showed a non-random X-chromosome inactivation pattern, indicating clonality. All three clonal cases were cord capillary hemangiomas. Our study has shown that in spite of considerable morphologic heterogeneity and overlapping features, classical hamartoma and cord capillary hemangioma and myoid angioendothelioma are different in terms of their vascular and stromal composition. Clonality analysis supports a true neoplastic origin for the cord capillary hemangioma. A larger study using additional immunohistochemical and molecular studies is necessary to further evaluate the biological significance of the current findings.
    Modern Pathology 01/2011; 24(1):108-16. · 5.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.
    Nature Immunology 09/2010; 11(9):836-45. · 26.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have shown previously that cancer/testis (CT) antigen, CT45, is expressed in various epithelial cancers at a frequency of <5% to approximately 35%. In this study, the protein expression of CT45 was examined in non-Hodgkin B-cell lymphomas and classical Hodgkin lymphoma by immunohistochemical analysis. Serological response to CT45 was also evaluated by ELISA using CT45 recombinant protein and sera from patients with Hodgkin lymphoma. None of the 80 low-grade B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma, expressed CT45. In comparison, CT45 was expressed in 28 of 126 (22%) diffuse large B-cell lymphomas (DLBCL). A remarkably high percentage (42/72, 58%) of classical Hodgkin lymphoma contained CT45-positive Reed-Sternberg cells. Nodular sclerosis and mixed-cellularity subtypes had similar frequency of CT45 expression, but most EBV-positive cases were CT45 negative. Gray-zone lymphoma (cases with features of both DLBCL and classical Hodgkin lymphoma) also showed frequent (64%) CT45 expression. Evaluation of reactive lymphoid tissues showed scattered CT45-positive lymphocytes in a single case of florid follicular hyperplasia, raising the possibility that this case was an evolving malignancy. Despite frequent CT45 expression, only 1 of 67 Hodgkin lymphoma patients had detectable anti-CT45 antibodies in the serum, suggesting that the immune response to CT45 may be suppressed. In conclusion, classical Hodgkin lymphoma has the highest frequency of CT45 expression among all malignancies tested to date, the frequency of CT45 expression in DLBCL is similar to that seen in epithelial cancers, and low-grade non-Hodgkin B-cell lymphomas do not express CT45.
    Proceedings of the National Academy of Sciences 02/2010; 107(7):3093-8. · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) represents a clinically heterogeneous disease. Models based on immunohistochemistry predict clinical outcome. These include subdivision into germinal center (GC) versus non-GC subtypes; proliferation index (measured by expression of Ki-67), and expression of BCL-2, FOXP1, or B-lymphocyte-induced maturation protein (Blimp-1)/PRDM1. We sought to determine whether immunohistochemical analyses of biopsies from patients with DLBCL having HIV infection are similarly relevant for prognosis. We examined 81 DLBCLs from patients with AIDS in AMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) and AMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plus rituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data, Epstein-Barr virus (EBV) positivity, and CD4 counts. The GC and non-GC subtypes of DLBCL did not differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could be found in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival. Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients with AIDS-related DLBCL. These data indicate that with current treatment strategies for lymphoma and control of HIV infection, commonly used immunohistochemical markers may not be clinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical marker was found to be Ki-67, where a higher proliferation index was associated with better survival, suggesting a better response to therapy in patients whose tumors had higher proliferation rates.
    Journal of Clinical Oncology 09/2009; 27(30):5039-48. · 18.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.
    Nature Immunology 09/2009; 10(9):1008-17. · 26.20 Impact Factor
  • Source
    HSS Journal 08/2009; 5(2):169-77.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among the diffuse lymphomas of B-cell origin, we have encountered one variant displaying blastoid features that morphologically mimic lymphoblastic lymphoma, the blastoid variant of mantle cell lymphoma, and the so-called blastoid transformation of follicular lymphoma. To better characterize this entity, we studied eight cases morphologically, immunohistochemically, and by fluorescence in situ hybridization (FISH) for cytogenetic abnormalities commonly associated with follicular lymphoma and B-cell lymphomas exhibiting high-grade histological features. All eight cases were presented as de novo neoplasms, and displayed an entirely diffuse (five cases) or only minimal follicular (three cases) growth pattern. The neoplastic lymphoid cells were of medium size with round nuclei, fine chromatin, inconspicuous nucleoli, and high mitotic rate; they expressed CD10, BCL6, and BCL2-a phenotype consistent with follicle center cell origin. A proportion of cases expressed MUM1. Their lack of TdT and CYCLIN D1 distinguished them from lymphoblastic lymphoma and the blastoid mantle cell lymphoma, respectively. The neoplastic lymphoid cells consistently expressed CD43 (seven of eight cases) and occasionally other T-cell-associated antigens, including CD5, CD7, CD8, and CD57. Although all cases overexpressed BCL2, t(14;18) was not detected in any of the five cases examined by FISH; instead, extra copies of chromosome 18 were found in four of five cases. Finally, other cytogenetic abnormalities, including structural abnormalities of BCL6 (allelic loss/gain, rearrangement), monosomy 7, del(13)(q14), and MYC allelic loss, were frequently detected. The combination of a B-cell CD10+ BCL6+ BCL2+ phenotype in the presence of structural abnormalities of BCL6 is consistent with a follicular center cell derivation for our cases. The lack of t(14;18) seen in our cases, although rare in most cases of follicular lymphoma, has been nevertheless reported in cases of follicular lymphoma with a predominantly diffuse growth pattern. The molecular pathogenesis, clinical manifestations, and prognostic significance of these lesions remain to be elucidated.
    Modern Pathology 08/2009; 22(11):1507-17. · 5.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells express together with IgM through alternative RNA splicing. Here we report active T cell-dependent and T cell-independent IgM-to-IgD class switching in B cells of the human upper respiratory mucosa. This process required activation-induced cytidine deaminase (AID) and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell-stimulating factors, including cathelicidin, interleukin 1 (IL-1), IL-4 and B cell-activating factor (BAFF), after IgD crosslinking. By showing dysregulation of IgD class-switched B cells and 'IgD-armed' basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.
    Nature Immunology 07/2009; 10(8):889-98. · 26.20 Impact Factor

Publication Stats

1k Citations
320.84 Total Impact Points

Institutions

  • 2014
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2013
    • University of Texas MD Anderson Cancer Center
      • Department of Hematopathology
      Houston, TX, United States
  • 2012
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 2010–2012
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States
  • 2002–2011
    • Weill Cornell Medical College
      • Department of Pathology and Laboratory Medicine
      New York City, NY, United States
  • 2009
    • University of Chicago
      Chicago, Illinois, United States
  • 2002–2009
    • Cornell University
      • Department of Pathology and Laboratory Medicine
      Ithaca, NY, United States