Recurrent non-random balanced chromosomal translocation, usually involving the immunoglobulin heavy chain (IgH) gene or an immunoglobulin light chain gene and a proto-oncogene, which results in the overexpression of the latter under the control of an enhancer or promoter of the former, is a hallmark of many types of non-Hodgkin lymphoma (NHL) of B-cell origin. However, translocations between IgH and the immunoglobulin (Ig) light chain lambda gene (IgL), namely, a t(14;22)(q32;q11), have rarely been described in B-cell NHL. Herein we report the first case of marginal zone B-cell lymphoma harboring a t(14;22)(q32;q11) as its sole genetic abnormality in a patient with a 12-year history of systemic lupus erythematosus (SLE). Other interesting findings of this case include: 1) the neoplastic B-cells lack expression of both surface and cytoplasmic Ig light chain as revealed by flow cytometry and 2) monoclonal rearrangement of Ig light chain kappa (IgK) only due to k-deleting element (kde) recombination event. This case illustrates the necessity of utilizing a multi-modality approach in the diagnosis of B-cell NHL.

Amino acid metabolism is involved in diverse cellular functions, including cell survival and growth; however, it remains unclear how it regulates normal haematopoiesis versus leukaemogenesis. Here, we report that knockout of solute carrier family 1 member 5 (Slc1a5/ASCT2), a transporter of neutral amino acids, especially glutamine, results in mild-to-moderate defects in bone marrow and mature blood cell development under steady-state conditions. In contrast, constitutive or induced deletion of Slc1a5 decreases leukaemia initiation and maintenance driven by oncogene MLL-AF9 or phosphatase and tensin homologue (Pten) deficiency. Survival of leukaemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukaemia development and progression in xenograft models of human acute myeloid leukaemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine (Leu) influx and mechanistic target of rapamycin (mTOR) signalling, and induces apoptosis in leukaemic cells. Given the substantial difference in reliance on ASCT2-mediated amino acid metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukaemia.

SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells. Although SIRT3 expression levels were increased in the gastric tumor tissues compared to the adjacent non-tumor tissues, SIRT3 positive cancer cells were more frequently detected in the intestinal type gastric cancers than the diffuse type gastric cancers, indicating that SIRT3 is linked with subtypes of gastric cancer. Overexpression of SIRT3 promoted cell proliferation and enhanced ATP generation, glucose uptake, glycogen formation, MnSOD activity and lactate production, which were inhibited by SIRT3 knockdown, indicating that SIRT3 plays a role in reprogramming the bioenergetics in gastric tumor cells. Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity. In consistence, a cluster of glycolysis-associated genes was upregulated in the SIRT3-overexpressing gastric tumor cells. Thus, in addition to the well-documented SIRT3-mediated mitochondrial homeostasis in normal cells, SIRT3 may enhance glycolysis and cell proliferation in SIRT3-expressing cancer cells.

Hematogones are immature normal B cell precursors with a characteristic immunophenotype profile on flow cytometry that typically do not express surface immunoglobulin light chains. In this report, we describe a case in which the hematogones exhibit light chain restriction. Our patient was a 4-year-old boy with a complicated medical history involving treatment for a presumed bilateral Wilms tumor of the kidney that on later resection was diagnosed as Burkitt lymphoma. Flow cytometry analysis of his bone marrow revealed a small distinct population of cells expressing dim cluster of differentiation (CD)10, CD19, CD22, CD38, dim CD58, human leukocyte antigen-D related (HLA-DR), and dim CD45, which are characteristic of hematogones. These cells, however, demonstrated dim surface immunoglobulin lambda light-chain restriction. Molecular study results for immunoglobulin heavy and kappa light-chain gene rearrangements were negative. We present this case to raise awareness of the potential pitfalls of working up bone marrow for involvement by B cell lymphoproliferative disorder.

Human histocompatibility leukocyte antigen (HLA)-DO, a lysosomal resident major histocompatibility complex class II molecule expressed in B cells, has previously been shown to be a negative regulator of HLA-DM peptide loading function. We analyze the expression of DO in human peripheral blood, lymph node, tonsil, and bone marrow to determine if DO expression is modulated in the physiological setting. B cells, but not monocytes or monocyte-derived dendritic cells, are observed to express this protein. Preclearing experiments demonstrate that ∼50% of HLA-DM is bound to DO in peripheral blood B cells. HLA-DM and HLA-DR expression is demonstrated early in B cell development, beginning at the pro-B stage in adult human bone marrow. In contrast, DO expression is initiated only after B cell development is complete. In all situations, there is a striking correlation between intracellular DO expression and cell surface class II-associated invariant chain peptide expression, which suggests that DO substantially inhibits DM function in primary human B cells. We report that the expression of DO is markedly downmodulated in human germinal center B cells. Modulation of DO expression may provide a mechanism to regulate peptide loading activity and antigen presentation by B cells during the development of humoral immune responses.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) represents a distinct subtype of mature B-cell neoplasms in the most recent WHO classification of hematolymphoid neoplasms. It has a characteristic immunoblastic/plasmablastic morphology, a distinct immunophenotypic profile and recurrent cytogenetic/molecular genetic abnormalities, and has been reported in both the adult and pediatric populations. With the advent of new ALK inhibitors for possible targeted therapy clinical trials, it is important to recognize this new entity, particularly in the pediatric population because the prognosis is worse than the more common ALK+ anaplastic large cell lymphoma. Though rare, awareness of its existence will avoid potential misdiagnosis and facilitate appropriate management.

Systemic mastocytosis is a neoplastic proliferation of mast cells that frequently presents with associated clonal hematological non-mast cell lineage disease. Myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene are a heterogenous group of rare and aggressive hematopoietic stem cell disorders. About a dozen of chromosome changes involving the FGFR1 gene, presenting as myeloid or lymphoid neoplasms, have been described in the literature. To date, only 2 cases of myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene have been reported in association with systemic mastocytosis, one with t(8;13) and one with t(8;17) involving the FGFR1 gene. Here we describe another case of myeloproliferative neoplasm with chromosome translocation t(8;19) involving FGFR1 gene associated with systemic mastocytosis.

Asparaginyl endopeptidase (AEP or legumain) is a lysosomal cysteine protease that cleaves protein substrates on the C-terminal side of asparagine. AEP plays a pivotal role in the endosome/lysosomal degradation system and is implicated in antigen processing. The processing of the lysosomal proteases cathepsins in kidney is completely defective in AEP-deficient mice with accumulation of macromolecules in the lysosomes, which is typically seen in lysosomal disorders. Here we show that mutant mice lacking AEP develop fever, cytopenia, hepatosplenomegaly, and hemophagocytosis, which are primary pathological manifestations of hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HLH). Moreover, AEP deficiency provokes extramedullary hematopoiesis in the spleen and abnormally enlarged histiocytes with ingested red blood cells (RBCs) in bone marrow. Interestingly, RBCs from AEP-null mice are defective in plasma membrane components. Further, AEP-null mice display lower natural killer cell activity, but none of the major cytokines is substantially abnormal. These results indicate that AEP might be a previously unrecognized component in HLH pathophysiology.

The prognostic significance of flow cytometric immunophenotyping (FCI) in acute myeloid leukemia (AML) has been controversial. In this study, we re-investigated the possible role of FCI in the prediction of AML relapse following standard chemotherapy. A total of 209 AML cases with follow-up information were analyzed. Among those, 78 cases were in remission (M:F=44/34; mean age of 48.9 years) and 131 had relapse (M:F=71/60; mean age of 51.3 years). The expression of CD34, HLA-DR or a combination of both was significantly different between the remission and relapse groups for all AML as well as AML without t(15;17). None of the pammyeloid markers or their combinations analyzed was found to correlate with treatment outcomes. Complex cytogenetic abnormalities were more likely associated with relapse group than with remission group, but were not statistically significant after excluding AML with t(15;17). In conclusion, FCI is useful in predicting treatment outcome and disease relapse in AML.

Reported herein is a case of composite small lymphocytic lymphoma (SLL) and extramedullary myeloid tumor (EMT) occurring in the same lymph node. Routine morphologic examination revealed a diffuse proliferation of small mature lymphocytes with numerous irregularly dispersed nodules, closely resembling SLL with prominent proliferation centers or Richter's transformation. Flow cytometric immunophenotyping and immunohistochemical stains demonstrated the presence of SLL cells as well as myeloblasts, confirming the diagnosis of a composite SLL and EMT. Conventional cytogenetics and fluorescence in situ hybridization studies revealed inversion 16 chromosome involving the core binding factor beta and myosin heavy chain 11 genes, characteristic of acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16) or t(16;16) [CBFbeta/MYH11]. In conclusion, the occurrence of SLL and EMT in the same lymph node is rare and multiparameter approach is essential for a definitive diagnosis.