Biomedical subjects

Jeffery L Kutok

Publications and source records attributed to Jeffery L Kutok.

17 recordsLinked to original sources

PubMed2003

The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.

Mediastinal large B-cell lymphoma (MLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that characteristically presents as localized tumors in young female patients. Although MLBCL has distinctive pathologic features, it clinically resembles the nodular sclerosis subtype of classical Hodgkin lymphoma (cHL). To elucidate the molecular features of MLBCL, we compared the gene expression profiles of newly diagnosed MLBCL and DLBCL and developed a classifier of these diseases. MLBCLs had low levels of expression of multiple components of the B-cell receptor signaling cascade, a profile resembling that of Reed-Sternberg cells of cHL. Like cHLs, MLBCLs also had high levels of expression of the interleukin-13 (IL-13) receptor and downstream effectors of IL-13 signaling (Janus kinase-2 [JAK2] and signal transducer and activator of transcription-1 [STAT1]), tumor necrosis factor (TNF) family members, and TNF receptor-associated factor-1 (TRAF1). Increased expression of STAT1 and TRAF1 in MLBCL was confirmed by immunohistochemistry. Given the TRAF1 expression and known link to nuclear factor-kappa B (NF- kappa B), MLBCLs were also evaluated for nuclear translocation of c-REL protein. In almost all cases, c-REL was localized to the nucleus, consistent with activation of the NF-kappa B pathway. These studies identify a molecular link between MLBCL and cHL and a shared survival pathway.

Active Transport, Cell Nucleus↗

PubMed2003

Bad-deficient mice develop diffuse large B cell lymphoma.

The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.

Animals↗

PubMed2003

The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity.

Members of the DTX (Deltex) family act as Notch signaling modifiers and may also regulate transcription through interactions with specific transcription factors. DTX proteins have a basic N terminus; a central proline-rich region; and a C-terminal RING finger domain, a motif often found in ubiquitin-protein isopeptide ligases (E3). Recently, we identified and characterized a unique diffuse large B-cell lymphoma risk-related gene named BAL (B aggressive lymphoma). Using a yeast two-hybrid screen for BAL-binding partners, we have now identified a novel protein termed BBAP (B-lymphoma- and BAL-associated protein). Although BBAP has a unique N terminus, the C-terminal region is highly homologous to that of DTX family members. Herein, we report that BBAP and the human family of DTX proteins (DTX1, DTX2, and DTX3) function as E3 ligases based on their capacity for self-ubiquitination. DTX family members homodimerize and heterodimerize in vivo, suggesting that physical interactions between various DTX family members modify E3 activity and/or substrate availability. Consistent with this idea, BBAP and DTX1 associate via their unique N termini, resulting in enhanced self-ubiquitination.

Amino Acid Sequence↗

PubMed2003

Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.

The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor generates potent, specific, and long-lasting antitumor immunity through improved tumor antigen presentation by dendritic cells and macrophages. A phase I clinical trial of this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T and B cell infiltrates that effectuated substantial tumor necrosis and fibrosis. To delineate the target antigens of this vaccine-stimulated tumor destruction, we screened a melanoma cDNA expression library with postimmunization sera from a long-term responding patient (K030). High-titer IgG antibodies recognized melanoma inhibitor of apoptosis protein (ML-IAP), a caspase antagonist containing a single baculoviral IAP repeat and a COOH-terminal RING domain. Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching. Moreover, lymphocyte infiltrates in necrotic metastases included CD4+ and CD8+ T cells specific for ML-IAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis. Whereas melanoma cells in densely infiltrated lesions showed strong ML-IAP expression by immunohistochemistry, lethal disease progression was associated with the loss of ML-IAP staining and the absence of lymphocyte infiltrates. These findings demonstrate that ML-IAP can serve as a target for immune-mediated tumor destruction, but that antigen-loss variants can accomplish immune escape.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Myc-induced T cell leukemia in transgenic zebrafish.

The zebrafish is an attractive model organism for studying cancer development because of its genetic accessibility. Here we describe the induction of clonally derived T cell acute lymphoblastic leukemia in transgenic zebrafish expressing mouse c-myc under control of the zebrafish Rag2 promoter. Visualization of leukemic cells expressing a chimeric transgene encoding Myc fused to green fluorescent protein (GFP) revealed that leukemias arose in the thymus, spread locally into gill arches and retro-orbital soft tissue, and then disseminated into skeletal muscle and abdominal organs. Leukemic cells homed back to the thymus in irradiated fish transplanted with GFP-labeled leukemic lymphoblasts. This transgenic model provides a platform for drug screens and for genetic screens aimed at identifying mutations that suppress or enhance c-myc- induced carcinogenesis.

Animals↗

PubMed2003

Proapoptotic BID is required for myeloid homeostasis and tumor suppression.

The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a "BH3-only" molecule, amplifies death receptor signals connecting the extrinsic to intrinsic pathways by triggering the mitochondrial pathway of apoptosis. Bid-deficient mice, as they age, spontaneously develop a myeloproliferative disorder, which progresses from myeloid hyperplasia to a fatal, clonal malignancy closely resembling chronic myelomonocytic leukemia (CMML). Thus, an apoptotic defect can result in myeloid leukemogenesis. Premalignant Bid-/- myeloid precursor cells are resistant to death receptor-induced apoptosis. Furthermore, a competitive reconstitution assay demonstrates that Bid-deficient long-term repopulating cells give rise to expanded myelomonocytic cells in vivo. Surprisingly, a single BH3-only molecule operating in the extrinsic death receptor pathway proved essential in vivo for physiologic cell death required to maintain myeloid homeostasis. Moreover, progression to CMML indicates that an upstream BH3-only molecule, BID, is required to suppress tumorigenesis.

Animals↗

PubMed2003

Splenic vascular tumors.

Splenic vascular tumors are uncommon and are more typically encountered as benign incidental findings. By contrast, splenic angiosarcoma may present acutely and dramatically and typically pursues a very aggressive clinical course. Vascular tumors in the spleen may show conventional endothelial, specialized endothelial (sinusoidal/littoral cell) or lymphatic differentiation and there is morphologic overlap between some of the currently defined diagnostic categories, within which benign, intermediate, and malignant subsets are recognized. The greatest problem in trying to better define and analyze these tumors is the availability of only relatively small case numbers. This overview describes the diagnosis and differential diagnosis of splenic vascular tumors as presently understood.

Hemangioendothelioma↗

PubMed2003

MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP.

The MOZ-TIF2 fusion is associated with acute myeloid leukemia (AML) with inv(8)(p11q13). MOZ is a MYST family histone acetyltransferase (HAT), whereas TIF2 is a nuclear receptor coactivator that associates with CREB binding protein (CBP). Here we demonstrate that MOZ-TIF2 has transforming properties in vitro and causes AML in a murine bone marrow transplant assay. The C2HC nucleosome recognition motif of MOZ is essential for transformation, whereas MOZ HAT activity is dispensable. However, MOZ-TIF2 interaction with CBP through the TIF2 CBP interaction domain (CID) is essential for transformation. These results indicate that nucleosomal targeting by MOZ and recruitment of CBP by TIF2 are critical requirements for MOZ-TIF2 transformation and indicate that MOZ gain of function contributes to leukemogenesis.

Acetyltransferases↗

PubMed2003

PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.

FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.

Animals↗

PubMed2003

Langerhans cell histiocytosis involving the thymus. A case report and review of the literature.

Langerhans cell histiocytosis (LCH) is a neoplastic proliferation of Langerhans cells that occurs in a range of nodal and extranodal sites. Scattered reports of LCH within the thymus exist, typically among children within the setting of multifocal, multisystem disease. Rare cases of isolated LCH involving the thymus have occurred in adult patients with myasthenia gravis. We report a case of unifocal LCH involving the thymus in a middle-aged woman with a history of a resected leiomyosarcoma but no evidence of myasthenia gravis. Computed tomographic scans revealed an anterior mediastinal mass, which was excised and measured 9.0 cm. Histologic and immunophenotypic findings (CD1a, S100, and Fascin positive and CD68 negative) were consistent with LCH. To our knowledge, this is the first example of LCH occurring in a patient with a history of soft tissue sarcoma and one of the rare reported examples of LCH presenting as a large isolated lesion in the thymus of a nonmyasthenic adult.

Female↗

PubMed2002

Molecular biology of anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma.

Anaplastic large-cell lymphoma (ALCL) provides an excellent example of how molecular insights into tumor pathogenesis are influencing and improving tumor classification. ALCL was described initially as a subtype of T-cell/null-cell lymphoma characterized by unusual tumor cell morphology and the expression of CD30. However, it was soon recognized that a subset of ALCLs contained chromosomal translocations involving anaplastic lymphoma kinase (ALK), a novel receptor tyrosine kinase gene. These rearrangements create chimeric genes encoding self-associating, constitutively active ALK fusion proteins that activate a number of downstream effectors, including phospholipase C-gamma, phosphoinositol 3'-kinase, RAS, and signal transducer and activator of transcription proteins, all of which seem potentially important in cellular transformation. Not all tumors classified as ALCLs have ALK rearrangements and, conversely, ALK rearrangements occur in lymphomas of widely varying morphology. Hence, only molecular markers can reliably identify ALK+ ALCL. The importance of doing so is reflected by clinical studies suggesting that ALK+ ALCLs have a significantly better prognosis than other aggressive peripheral T-cell or B-cell lymphomas, including ALK- ALCLs. The unique molecular pathogenesis of ALK+ ALCL is likely to lead to novel therapeutic approaches directed at specific inhibition of ALK or downstream effectors.

Anaplastic Lymphoma Kinase↗

PubMed2002

A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9.

Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.

Animals↗

PubMed2002

Fine-needle aspiration cytology of lymphoproliferative disorders in the immunosuppressed patient: the diagnostic utility of in situ hybridization for Epstein-Barr virus.

We examined the diagnostic utility of fine-needle aspiration (FNA) in the immunosuppressed patient with particular attention to the value of in situ hybridization for Epstein-Barr virus encoded RNA (EBER), a test frequently performed on tissue sections in this setting. Six patients with adenopathy were identified: three with prior solid organ transplantation, two with prior bone marrow transplantation, and one with human immunodeficiency virus. Cytologic findings in involved tissues were positive for non-Hodgkin's lymphoma in one case, suspicious or atypical in three cases, negative/reactive in one case, and nondiagnostic in one case due to insufficient material. Two aspirates had a polymorphous lymphoid appearance; three showed predominantly monomorphous lymphoid morphology. Retrospectively, 4/4 FNA cell blocks were positive for EBER in a large proportion of atypical lymphoid cells. Together with the cytologic findings, EBER detection allows for more specific classification of these FNA samples as EBV-associated lymphoid proliferations.

Adult↗

PubMed2002

Expression of geminin as a marker of cell proliferation in normal tissues and malignancies.

Geminin interacts with a DNA replication initiation factor, Cdt1p, to suppress initiation of DNA replication in a Xenopus egg extract based cell-free system, leading to the expectation that the protein acts as an inhibitor of cell proliferation. Immunohistochemistry and immunoblotting for geminin, however, reveals that the protein is expressed specifically in proliferating lymphocytes and epithelial cells. This pattern is in contrast to the expression of a bona fide cell cycle inhibitor like p21/WAF1 that is specifically expressed in quiescent cells. Geminin is widely expressed in several malignancies and the number of geminin-expressing cells is directly proportional to the cell proliferation index as measured by Ki-67 expression. Therefore, instead of being a suppressor of cell proliferation, geminin expression is positively correlated with cell proliferation. Consistent with this observation, transient overexpression of wild-type geminin in cancer cells in culture did not produce a cell cycle block. A point mutation in the destruction box of geminin, however, results in a protein that is stabilized in G(1) and capable of arresting cells at the G(1)-S transition.

Biomarkers↗

PubMed2002

Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of patients with very different five-year overall survival rates (70% versus 12%). The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4).

Proliferative states such as chronic inflammation, ischemic diseases, and cancer are often accompanied by intense angiogenesis, a highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, and maturation. Aspirin-triggered lipoxins (ATLs), the 15R enantiomeric counterparts of lipoxins (LXs), are endogenous mediators generated during multicellular responses that display potent immunomodulatory actions. Herein, we report a novel action for the ATL stable analog 15-epi-16-(para-fluoro)-phenoxy-lipoxin A(4) (denoted ATL-1), which proved to be a potent inhibitor of angiogenesis. This ATL inhibited endothelial cell proliferation in the 1 to 10 nM range by approximately 50% in cells stimulated with either vascular endothelial growth factor (VEGF) at 3 ng/ml or leukotriene D(4) at 10 nM. In addition, ATL-1 (in a 10-100 nM range) inhibited VEGF (3 ng/ml)-induced endothelial cell chemotaxis. In a granuloma in vivo model of inflammatory angiogenesis, ATL-1 treatment (10 microg/mouse) reduced by approximately 50% the angiogenic phenotype, as assessed by both vascular casting and fluorescence. Together, these results identify a novel and potent previously unappreciated action of aspirin-triggered 15-epi-LX.

Angiogenesis Inhibitors↗

PubMed2002

Human HTm4 is a hematopoietic cell cycle regulator.

Proper control of cell cycle progression is critical for the constant self-renewal, differentiation, and homeostasis of the hematopoietic system. Cells of all types share the common cell cycle regulators. The different expression patterns of common regulators, in a broad sense, define cell-type or lineage specificity. However, there remains the possibility of hematopoietic cell cycle regulators tailored to the demands of the hematopoietic system. Here we describe a novel protein, HTm4, which serves as a hematopoietic cell cycle regulator. Our data indicate that HTm4 is expressed in hematopoietic tissues and is tightly regulated during the differentiation of hematopoietic stem cells. It binds to cyclin-dependent kinase-associated (CDK-associated) phosphatase-CDK2 (KAP-CDK2) complexes, and the three proteins demonstrate similar patterns of cellular expression in human lymphoid tissues. HTm4 stimulates the phosphatase activity of KAP, and its C-terminal region is required for binding to KAP-CDK2 complexes and the modulation of KAP activity. Overexpression of HTm4 can cause cell cycle arrest at the G(0)/G(1) phase. Thus, HTm4 is a novel hematopoietic modulator for the G(1)-S cell cycle transition.

Amino Acid Sequence↗