Constitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/ enhancer-binding protein ␣ (C/EBP␣) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBP␣ and PU. IntroductionFMS-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase family that also includes c-kit receptor tyrosine kinase (KIT) and FMS, 2 other receptors with important roles in hematopoiesis. FLT3 is preferentially expressed on hematopoietic stem/progenitor cells and plays a role in both differentiation and proliferation. 1 Somatic mutations of FLT3 involving internal tandem duplications (ITDs) of the juxtamembrane domain or D835 point mutations in the activation loop have been identified in approximately 17% to 34% and 7% of acute myeloid leukemia (AML) patients, respectively. [2][3][4][5][6] The ITD mutations appear to activate the tyrosine kinase domain of the FLT3 receptor through constitutive dimerization and result in autophosphorylation of the receptor. 7 Constitutively activated FLT3 contributes to leukemic transformation and portends an especially poor prognosis for patients with this mutation. [8][9][10] Uncontrolled proliferation, antiapoptotic advantages, and a block in differentiation characterize acute leukemia. The role of FLT3/ITDs in giving a proliferative and antiapoptotic advantage to cells has been reported. 11,12 Recently, we demonstrated that FLT3/ ITD expression also contributes to a blockage of granulocyte colony-stimulating factor (G-CSF)-mediated differentiation in 32Dcl3 (32D) cells. 13 However, the mechanism by which this block occurs is not known.The development of mature granulocytes from hematopoietic progenitor cells is regulated by a complex network of transcription factors. 14 The family of CCAAT/enhancer-binding proteins (C/ EBPs) plays a key role in myeloid differentiation. One member of the C/EBP family, C/EBP␣, is prominently expressed in early myeloid progenitor cells, and its expression decreases as these progenitors further differentiate into mature granulocytes. 15 Absence of neutrophil development and G-CSF signaling is observed in C/EBP␣-deficient mice. 16 Overexpression of C/EBP␣ in the HL-60 and U937 human leukemia cell lines or murine 32D cells leads to the development of neutrophils. 17,18 Recently, mutations in the C/EBP␣ gene have been iden...

The inverse association between aspirin, but not other NSAIDs, and Hodgkin's lymphoma suggests that NF-kappaB signaling may play a key role in Hodgkin's lymphoma pathogenesis.

Most cases of acute leukemia can be assigned to the myeloid, B or T lineage. In a few cases, definitive assignment cannot be achieved because blasts express antigens of more than one lineage. A subset of these, referred to as acute bilineal leukemias (aBLLs), is characterized by the presence of more than one population of blasts, each comprising a single lineage. We identified 19 cases of aBLL, including 10 mixed T and myeloid (T-My) and nine mixed B and myeloid (B-My); no mixed B and T cases were identified. Cytogenetic data were available for 16 patients. Three of seven patients with B-My had a t(9;22)(q34q11.2), two had 11q23 translocations and one had del(9). Two of nine patients with T-My had 2p13 translocations; five had other unrelated abnormalities. Of 16 patients with outcome data, only six achieved complete remission and only two remain free of disease 2.5 and 4.5 years after chemotherapy or stem cell transplantation. aBLL is a rare disease that combines B or T and myeloid blasts. Cytogenetic abnormalities of t(9;22) and 11q23 are common in, and may be restricted to, B-My cases, while T-My cases have frequent but generally nonrecurring abnormalities. Both types of aBLL are associated with poor outcome.

Multiparameter flow cytometry may be used to detect minimal residual disease in acute leukemia because leukemic cells often display aberrant phenotypes when compared to normal cells. One limitation of this approach in B-precursor ALL is that leukemic phenotypes are often qualitatively similar to normal marrow B progenitors, though it has long been recognized that the latter show a predictable pattern of antigen expression with differentiation. In this study we used four-color flow cytometry to define precisely the patterns of normal antigen expression on a series of normal bone marrows using two different four-color combinations of antibodies: CD19-APC/CD45-perCP/CD20-PE/CD10-FITC; and CD19-APC/CD45-perCP/CD9-PE/CD34-FITC. A series of dual parameter displays were created in which normal B precursors occupied predictable regions. We then tested these antibody combinations on a series of 82 cases of B-precursor ALL and found that in 76/82 cases (93%) the first combination demonstrated an abnormal population on at least one of the dual parameter displays, and that 72/77 cases tested (94%) showed an abnormality with the second combination. When taken together, 81/82 cases (99%) showed an abnormality. When purified blasts were serially diluted into normal marrows we found a sensitivity of detection of 1 cell in 10 4 normal marrow cells provided sufficient CD19 + cells were acquired to visualize the abnormal population as a discrete cluster. Because the pattern of antigen expression in normals is very reproducible, it is possible to create a fixed set of geometrical regions to define the normal; this makes analysis of an unknown sample very straightforward. We conclude that our approach could be employed as a simple method for the detection of minimal residual disease in B-precursor ALL, and unlike many other methods should prove applicable to virtually all cases of this malignancy.

EBV-positive HL is more common among individuals who have markers of diminished cellular immunity and an abnormal EBV antibody response. EBV appears to participate in the etiology of EBV-positive HL but may not be involved in EBV-negative HL.

BACKGROUND Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with malignant gliomas. To investigate the pathogenesis of VTE and facilitate targeted prophylaxis strategies, the authors aimed to characterize VTE risk factors in these patients. METHODS The authors conducted a retrospective chart review of 130 adult patients with glioma who received their primary therapy at the Johns Hopkins Hospital (Baltimore, MD) between 1991 and 2001. Symptomatic VTE was confirmed by objective radiologic testing. The association between clinical and laboratory characteristics and VTE was assessed using parametric and nonparametric statistical tests and survival analysis. RESULTS VTE developed in 28 patients (21.5%) at a median of 4.8 months after diagnosis (interquartile range, 2.1–13.2). Patients with tumors > 5 cm were more likely to develop VTE than patients with smaller tumors (hazard ratio = 2.2; P = 0.04). For every year increase in age, the hazard ratios for thrombosis increased by 3% (P = 0.011). When stratified by ABO blood group, the hazard ratios for thrombosis were 2.7 and 9.4 for patients with blood groups A (P = 0.045) and AB (P < 0.0001), respectively, compared with patients with blood group O. No association was observed between VTE and the other patient characteristics analyzed. CONCLUSIONS Patient age, tumor size, and particularly ABO blood group are risk factors for VTE among patients with malignant gliomas. These findings may facilitate the development of a thrombosis risk score that will allow physicians to individualize VTE prophylaxis regimens. Cancer 2004. © 2004 American Cancer Society.

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