Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features.
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Adult↗
Biomedical subjects
R P Hasserjian
Publications and source records attributed to R P Hasserjian.
Quantitation of bacteria in bone marrow from patients with typhoid fever: relationship between counts and clinical features.
Enteric fever is the only bacterial infection of humans for which bone marrow examination is routinely recommended. A prospective study of the concentrations of bacteria in the bone marrow and their relationship to clinical features was conducted with 120 Vietnamese patients with suspected enteric fever, of whom 89 had confirmed typhoid fever. Ninety-three percent of the Salmonella enterica serovar Typhi samples isolated were resistant to ampicillin, chloramphenicol, and co-trimoxazole. For 81 patients with uncomplicated typhoid and satisfactory bone marrow aspirates, the number of serovar Typhi CFU in bone marrow aspirates was a median value of 9 (interquartile range [IQR], 1 to 85; range, 0.1 to 1,580) compared to 0.3 (IQR, 0.1 to 10; range, 0.1 to 399) CFU/ml in simultaneously sampled blood. The ratio of individual blood counts to bone marrow counts was 10 (IQR, 2.3 to 97.5). The number of bacteria in blood but not bone marrow was correlated inversely with the duration of preceding fever. Thus, with increasing duration of illness the ratio of bone marrow-to-blood bacterial concentrations increased; the median ratio was 4.8 (IQR, 1 to 27.5) during the first week compared with 158 (IQR, 60 to 397) during the third week. After lysing the host cells, the median ratio of viable bone marrow to blood increased, reflecting the higher concentration of intracellular serovar Typhi in the bone marrow. Effective antibiotic pretreatment had a significantly greater effect in reducing blood counts compared to bone marrow counts (P < 0.001). Thus, bacteria in the bone marrow of typhoid patients are less affected by antibiotic treatment than bacteria in the blood. The numbers of bacteria in bone marrow correlated negatively with the white blood cell (R = -0.3, P = 0.006) and platelet counts (R = -0.32, P = 0.01) and positively with fever clearance time after treatment (R = 0.4, P < 0.001). The bacterial load in bone marrow therefore may reflect the clinical course of the infection, and high levels may suppress neutrophil proliferation.
Adolescent↗
Acute erythremic myelosis (true erythroleukaemia): a variant of AML FAB-M6.
AIMS: Classic erythroleukaemia (acute myeloid leukaemia M6, or M6 AML) is defined as an excess of myeloblasts in an erythroid predominant background. Leukaemia variants in which the primitive blast cells are demonstrably erythroid are extremely rare and poorly characterised. Variably referred to as "true erythroleukaemia" or "acute erythremic myelosis", they are often included within the M6 AML category even though they do not meet strict criteria for this type of AML. METHODS: Two cases of acute erythroid neoplasia are presented with clinical, morphological, immunophenotypic, and cytogenetic analysis. RESULTS: Both patients presented with profound anaemia, one in a setting of long standing myelodysplasia. Bone marrow examination revealed a predominant population of highly dysplastic erythroid cells in both cases. In one case, the liver was infiltrated by neoplastic erythroid cells. Both patients died within four months of diagnosis. CONCLUSIONS: This report illustrates that cases of acute leukaemia occur in which the dominant neoplastic cell is a primitive erythroid cell without an accompanying increase in myeloblasts. This does not preclude the neoplastic clone originating in a multipotent haemopoietic stem cell, as suggested by cases arising in patients with myelodysplasia. Acute erythremic myelosis should be recognised as a distinct variant of M6 AML.
Adult↗
Recurrences in nodal T-cell lymphoma. Changes in histologic appearance and immunophenotype over the course of disease.
We examined the patterns of relapse or persistence in 37 cases of nodal peripheral T-cell lymphoma (PTCL) to address the morphologic and immunophenotypic findings. Relapses were documented in lymph node (25 cases) and/or a variety of extranodal sites at a mean of 21 months after presentation; several cases recurred as late as 13 years. Persistent bone marrow involvement was a feature of angioimmunoblastic lymphoma (AIL) and histiocyte-rich and small-cell tumors. Relapses in anaplastic tumors often involved unusual extranodal sites. The majority of relapsed PTCLs retained a similar histologic appearance, pattern of nodal involvement, and immunophenotype. Histologic progression, as assessed by increased numbers of large cells, was seen in 3 cases of AIL, in 1 case with an initial small cell morphologic appearance, and in 2 cases of PTCL with an initial mixed small and large cell appearance. Immunostains for T-cell activation markers showed increased immunoreactive cells in 5 of the 6 cases, whereas increased numbers of p53-positive tumor cells were noted in 3 of the 6 cases. The discrete large cell transformation occasionally seen in B-cell lymphoma and extranodal T-cell lymphoma was not observed in these cases.
Adolescent↗
Thyroid hormones regulate hypertrophic chondrocyte differentiation and expression of parathyroid hormone-related peptide and its receptor during endochondral bone formation.
Hypothyroidism in children causes developmental abnormalities in bone and growth arrest, while thyrotoxicosis accelerates growth rate and advances bone age. To determine the effects of thyroid hormones on endochondral bone formation, we examined epiphyseal growth plates in control, hypothyroid, thyrotoxic, and hypothyroid-thyroxine (hypo-T4)-treated rats. Hypothyroid growth plates were grossly disorganized, contained an abnormal matrix rich in heparan sulfate, and hypertrophic chondrocyte differentiation failed to progress. These effects correlated with the absence of collagen X expression and increased parathyroid hormone-related protein (PTHrP) messenger RNA (mRNA) expression. In thyrotoxic growth plates, histology essentially was normal but PTHrP receptor (PTHrP-R) mRNA was undetectable. PTHrP is a potent inhibitor of hypertrophic chondrocyte differentiation that acts in a negative feedback loop with the secreted factor Indian hedgehog (Ihh) to regulate endochondral bone formation. Thyroid hormone receptor alpha1(TRalpha1), TRalpha2, and TRbeta1 proteins were localized to reserve zone progenitor cells and proliferating chondrocytes in euthyroid rat cartilage; regions in which PTHrP and PTHrP-R expression were affected by thyroid status. Thus, dysregulated Ihh/PTHrP feedback loop activity may be a key mechanism that underlies growth disorders in childhood thyroid disease.
Animals↗
High expression of CD23 in the proliferation centers of chronic lymphocytic leukemia in lymph nodes and spleen.
Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm composed of a heterogeneous mixture of cells, including small lymphocytes, prolymphocytes, and large transformed cells; these last cells appear to represent the proliferating compartment. CLL cells express, in addition to B cell markers, the transmembrane receptor CD23. CD23 functions as the receptor for IgE and also appears to play a role in controlling the growth and proliferation of lymphocytes. Its level of expression among the different cells in CLL has not been examined. In this study, we show that CD23 expression is much higher in the large transformed CLL cells than in the small lymphoid population. This may provide an explanation for the observed correlation between a circulating CD23 cleavage product (soluble CD23) and prognosis in CLL. In addition, we have shown that proliferation in splenic CLL occurs preferentially in the white pulp zones, even in cases in which both the white and red pulp are extensively infiltrated.
Aged↗
Spindle cell rhabdomyosarcoma (so-called) in adults: report of two cases with emphasis on differential diagnosis.
Spindle cell rhabdomyosarcoma (RMS) is a recently described variant of embryonal RMS that carries a relatively favorable prognosis when compared with other forms of RMS. To date, spindle cell RMS has been described only in children. The authors have identified two unusual cases occurring in adults using the following criteria: tumors composed mainly of fascicular, relatively monomorphic spindle-shaped cells that show unequivocal immunohistochemical and ultrastructural evidence of myogenic differentiation. The tumors were identified in a 38-year-old woman and a 56-year-old man, arising in the cheek and left hemidiaphragm, respectively. Both were treated with surgical resection and chemotherapy. The first patient died of uncontrolled local recurrence of her tumor at 27 months after diagnosis, and the second died of metastatic disease at 13 months follow-up. The tumors were composed mainly of fascicles of spindle cells with palely eosinophilic cytoplasm admixed diffusely with sparse polygonal, rounded, or strap-shaped rhabdomyoblasts with brightly eosinophilic cytoplasm and with cross-striations in the first case only. Immunostaining for muscle-related antigens showed staining for smooth-muscle actin (focal), pan-actin HHF-35, desmin, fast myosin, myoglobin, and MyoD1. Both cases were negative for S-100 protein. On electron microscopy, both cases showed neoplastic rhabdomyoblasts with clear-cut sarcomeric differentiation in many of the tumor cells. Spindle cell RMS poses special problems in differential diagnosis when arising in adults and should be distinguished from leiomyosarcoma, malignant peripheral nerve sheath tumor with heterologous rhabdomyoblastic differentiation (malignant Triton tumor), and fibrosarcoma. In view of the good prognosis afforded children with spindle cell RMS and in light of the chemoresponsive behavior of RMS in general, we feel that it is important to identify tumors that meet the criteria for spindle cell RMS occurring in the adult population. However, based on these two cases, it is possible that spindle cell RMS occurring in adults may not be associated with such a favorable outcome.
Actins↗
Oncogenic forms of NOTCH1 lacking either the primary binding site for RBP-Jkappa or nuclear localization sequences retain the ability to associate with RBP-Jkappa and activate transcription.
Truncated forms of the NOTCH1 transmembrane receptor engineered to resemble mutant forms of NOTCH1 found in certain cases of human T cell leukemia/lymphoma (T-ALL) efficiently induce T-ALL when expressed in the bone marrow of mice. Unlike full-sized NOTCH1, two such truncated forms of the protein either lacking a major portion of the extracellular domain (DeltaE) or consisting only of the intracellular domain (ICN) were found to activate transcription in cultured cells, presumably through RBP-Jkappa response elements within DNA. Both truncated forms also bound to the transcription factor RBP-Jkappa in extracts prepared from human and murine T-ALL cell lines. Transcriptional activation required the presence of a weak RBP-Jkappa-binding site within the NOTCH1 ankyrin repeat region of the intracellular domain. Unexpectedly, a second, stronger RBP-Jkappa-binding site, which lies within the intracellular domain close to the transmembrane region and significantly augments association with RBP-Jkappa, was not needed for oncogenesis or for transcriptional activation. While ICN appeared primarily in the nucleus, DeltaE localized to cytoplasmic and nuclear membranes, suggesting that intranuclear localization is not essential for oncogenesis or transcriptional activation. In support of this interpretation, mutation of putative nuclear localization sequences decreased nuclear localization and increased transcriptional activation by membrane-bound DeltaE. Transcriptional activation by this mutant form of membrane-bound DeltaE was approximately equivalent to that produced by intranuclear ICN. These data are most consistent with NOTCH1 oncogenesis and transcriptional activation being independent of association with RBP-Jkappa at promoter sites.
Amino Acid Sequence↗
Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.
Signaling through Notch receptors has been implicated in the control of cellular differentiation in animals ranging from nematodes to humans. Starting from a human expressed sequence tag-containing sequence resembling that of Serrate, the gene for a ligand of Drosophila melanogaster Notch, we assembled a full-length cDNA, now called human Jagged2, from overlapping cDNA clones. The full-length cDNA encodes a polypeptide having extensive sequence homology to Serrate (40.6% identity and 58.7% similarity) and even greater homology to several putative mammalian Notch ligands that have subsequently been described. When in situ hybridization was performed, expression of the murine Jagged2 homolog was found to be highest in fetal thymus, epidermis, foregut, dorsal root ganglia, and inner ear. In Northern blot analysis of RNA from tissues of 2-week-old mice, the 5.0-kb Jagged2 transcript was most abundant in heart, lung, thymus, skeletal muscle, brain, and testis. Immunohistochemistry revealed coexpression of Jagged2 and Notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human Jagged2 with murine C2C12 myoblasts inhibited myogenic differentiation, accompanied by increased Notch1 and the appearance of a novel 115-kDa Notch1 fragment. Exposure of C2C12 cells to Jagged2 led to increased amounts of Notch mRNA as well as mRNAs for a second Notch receptor, Notch3, and a second Notch ligand, Jagged1. Constitutively active forms of Notchl in C2C12 cells also induced increased levels of the same set of mRNAs, suggesting positive feedback control of these genes initiated by binding of Jagged2 to Notch1. This feedback control may function in vivo to coordinate differentiation across certain groups of progenitor cells adopting identical cell fates.
Amino Acid Sequence↗
Modulated expression of notch1 during thymocyte development.
The Notch gene family encodes transmembrane proteins that have been implicated in control of diverse cellular differentiation events in the fly, frog, and mouse. Mammalian Notch1 is expressed at high levels in thymus and is mutated in a subset of human T-cell acute lymphoblastic neoplasms, suggesting a role in T-cell differentiation. To investigate the patterns of expression of NOTCH1 protein in thymocytes of the developing and mature thymus, antibodies raised against NOTCH1 were used to perform immunohistochemical and flow cytometric analyses. Strong staining for NOTCH1 within the fetal murine thymus was observed as early as 13.5 days postcoitum. By 17.5 days postcoitum, preferential staining of superficial cortical thymocytes was observed, with weak staining of developing medulla. Flow cytometric analysis and immunohistochemical staining of flow-sorted cells confirmed that the highest levels of NOTCH1 expression in adult murine thymus were present in immature cortical thymocytes (CD24high, CD4-CD8-). In contrast, NOTCH1 expression was low or absent in more mature cortical thymocytes (CD24low, CD4+CD8+), whereas intermediate levels of expression were observed in CD4+CD8- and CD4-CD8+ cells. These data indicate a dynamic pattern of NOTCH1 expression during T-cell differentiation and suggest that downregulation of NOTCH1 may be required for maturation of cortical thymocytes.
Animals↗
Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.
Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chromosomal translocation; however, its role in oncogenesis has been unclear. Using a bone marrow reconstitution assay with cells containing retrovirally transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney leukemia virus long terminal repeat drives expression in most hematopoietic cell types, retroviruses encoding either form of the TAN1 protein induced clonal leukemias of exclusively immature T cell phenotypes in approximately 50% of transplanted animals. All tumors overexpressed truncated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprotein and suggest that truncation and overexpression are important determinants of transforming activity. Moreover, the murine tumors caused by TAN1 in the bone marrow transplant model are very similar to the TAN1-associated human tumors and suggest that TAN1 may be specifically oncotropic for T cells.
Animals↗
Clinicopathologic and cytogenetic analysis of malignant rhabdoid tumor of the central nervous system.
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Brain Neoplasms↗
Carcinoma of the thymus with clear-cell features. Report of eight cases and review of the literature.
We report eight cases of thymic carcinoma with clear-cell features and review the five previously reported cases. The tumor was composed of cells with clear cytoplasm and rather bland nuclear features, and showed a lobular or occasionally sheet-like growth pattern. Cytoplasmic glycogen was demonstrable in 92% of cases, whereas mucin was absent in all cases tested. The tumor cells were uniformly immunoreactive for low- and high-molecular-weight keratins and were reactive for epithelial membrane antigen in 22% of cases. The differential diagnosis includes mediastinal seminoma, parathyroid carcinoma, and metastatic clear-cell carcinoma. The diagnosis of primary thymic carcinoma depends on the exclusion of other primary sites clinically, particularly lung and kidney, and the demonstration of postivity for keratins and negativity for placental alkaline phosphatase. Thymic carcinoma with clear-cell features behaves as a high-grade thymic carcinoma: including our cases and the previously reported cases, nine of 13 patients (69%) are either dead of disease or have persistent disease at the latest follow-up. The importance of this entity is recognition of its aggressive clinical behavior and its distinction from other primary and metastatic clear-cell neoplasms of the mediastinum.
Adult↗