The ENL moiety of the childhood leukemia-associated MLL-ENL oncoprotein recruits human Polycomb 3.

The translocation t(11;19) is frequently found in acute leukemia in infants. This event truncates the proto-oncogene MLL and fuses the 5' end of MLL in frame with the ENL gene. ENL contributes a crucial protein-protein interaction domain to the resulting oncoprotein MLL-ENL. Here we show by yeast two-hybrid assays, GST-pull-down experiments and in a far western blot analysis that this domain is necessary and sufficient to recruit a novel member of the human Polycomb protein family (hPc3). hPc3 RNA was detected throughout the human hematopoietic system. Similar to other Polycomb proteins hPc3 acts as a transcriptional repressor. The ENL-hPc3 interaction was verified by mutual co-precipitation of the proteins from cell extracts. ENL and hPc3 tagged with fluorescent proteins co-localized in living cells in a nuclear dot pattern. An internal region of hPc3 was responsible for binding to ENL. Finally, hPc3 binds to the C-terminus of AF9, another common MLL fusion partner. The recruitment of a repressive function by ENL opens up a new insight into a possible mechanism of leukemogenesis by the fusion protein MLL-ENL.

Basal forebrain malformation with hyperhidrosis and hypothermia: variant of Shapiro's syndrome.

A 62-year-old woman presented with episodic sweating and shivering with reduced core temperature. Brain MRI demonstrated a basal forebrain malformation. Physiologic testing included EEG, SPECT, heat challenge, and autonomic testing. Glycopyrrolate aborted spells and raised core temperature. Hypothalamic dysregulation is likely the primary pathophysiology in the setting of other forebrain anomalies. These findings expand the structural abnormalities and treatment options within the temperature dysregulating conditions of Shapiro's syndrome and "diencephalic epilepsy."

An evaluation of JPEG and JPEG 2000 irreversible compression algorithms applied to neurologic computed tomography and magnetic resonance images. Joint Photographic Experts Group.

We performed visual comparison of 200 head magnetic resonance (MR) and 200 head computed tomography (CT) images compressed at two levels using standard Joint Photographic Experts Group (JPEG) irreversible compression and a preliminary version of the JPEG 2000 irreversible algorithm. Blinded evaluations by neuroradiologists compared original versus either JPEG or JPEG 2000. We found that this version of JPEG 2000 did not perform as well as the current JPEG for head CTs, but for MR images, JPEG 2000 performed as well or better. Around 7:1 compression ratio seemed to be a conservative point where there was no perceptible difference.

A theory on the natural history of colloid cysts of the third ventricle.

OBJECTIVE: Patients with third ventricular colloid cysts typically are diagnosed when they develop symptoms related to cerebrospinal fluid (CSF) obstruction at the foramen of Monro. However, the clinical and neuroimaging characteristics related to symptom development are poorly understood. METHODS: From January 1974 to June 1998, 155 patients with newly diagnosed colloid cysts were managed at our center. Eighty-seven patients (56%) were thought to have tumor-related symptoms, and they underwent surgery (resection, n = 74; ventriculoperitoneal shunting, n = 11; stereotactic aspiration, n = 2). Sixty-eight patients (44%) had colloid cysts thought to be asymptomatic, and observation with serial neuroimaging was recommended. Recursive partitioning was used to examine the association of patient and tumor characteristics with the development of cyst-related symptoms. RESULTS: Univariate analysis comparing symptomatic and asymptomatic patients revealed four factors associated with cyst-related symptoms: 1) younger patient age (44 yr versus 57 yr; P < 0.001); 2) cyst size (13 mm versus 8 mm; P < 0.001); 3) ventricular dilation (83% versus 31%; P < 0.001); and 4) increased signal on T2-weighted magnetic resonance images (44% versus 8%; P = 0.001). All four variables remained significant in a multivariate logistic regression model: patient age (P = 0.04; odds ratio, 1.0); cyst size (P = 0.04; odds ratio, 1.2); ventricular dilation (P = 0.02, odds ratio, 7.2); and increased signal on T2-weighted magnetic resonance images (P = 0.04; odds ratio, 2.7). The most significant variable was ventriculomegaly (yes versus no). Patients with normal-sized ventricles (n = 62) were further categorized by cyst size (< or = 10 mm versus > 10 mm). For patients with enlarged ventricles (n = 93), patient age (< or = 50 yr versus > 50 yr) was the most important variable. Patients older than 50 years also were split with respect to cyst size; patients aged 50 years or younger with enlarged ventricles were not affected by cyst size. The percentage of patients with cyst-related symptoms was 12, 50, and 85% in the three final patient classes, respectively. Multivariate analysis including the patient classes resulted in removal of the other significant variables from the model, whereas the patient classes remained significant (P < 0.0001; odds ratio, 6.3) for predicting patients with cyst-related symptoms. CONCLUSION: The patient and neuroimaging characteristics of the different patient classes support a theory on the natural history of colloid cysts. Patients with third ventricular colloid cysts become symptomatic when the tumor enlarges rapidly, causing CSF obstruction, ventriculomegaly, and increased intracranial pressure. Some cysts enlarge more gradually, however, allowing the patient to accommodate the enlarging mass without disruption of CSF flow, and the patient remains asymptomatic. In these cases, if the cyst stops growing, the patient can maintain a steady state between CSF production and absorption and may not require neurosurgical intervention.

ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+.

Translocations of the chromosomal locus 11q23 that disrupt the MLL gene (alternatively ALL-1 or HRX) are frequently found in children's leukemias. These events fuse the MLL amino terminus in frame with a variety of unrelated proteins. Up to date, 16 different fusion partners have been characterized and more are likely to exist. No general unifying property could yet be detected amongst these proteins. We show here that the frequent MLL fusion partner ENL at 19p13.1 interacts with the human homologue of the mouse Abl-Interactor 1 (ABI1) protein. ABI1 in turn, is fused to MLL in the t(10;11)(p11.2;q23) translocation. ABI1 was identified as an ENL binding protein by a yeast two-hybrid screen. The interaction of ENL and ABI1 could be verified in vitro by far-Western blot assays and GST-pulldown studies as well as in vivo by co-immunoprecipitation experiments. A structure-function analysis identified an internal region of ENL and a composite motif of ABI1 including an SH3 domain as mutual binding partners. These data introduce novel aspects that might contribute to the understanding of the process of leukemogenesis by MLL fusion proteins.

The leukemogenic fusion of MLL with ENL creates a novel transcriptional transactivator.

Translocations affecting the chromosomal locus 11q23 are hallmarks of infant leukemias. These events disrupt the MLL gene (also ALL-1 or HRX) and fuse the MLL amino terminus in frame with a variety of unrelated proteins. The ENL gene on 19p13.1 is a recurrent fusion partner of MLL. Whereas potential functions have been suggested for isolated domains of either MLL or ENL no experimental data exist for the biological properties of the complete chimeric MLL-ENL protein. We show here that the fusion of MLL with ENL creates a novel molecule that is a potent general transcriptional transactivator in transient reporter gene assays. MLL-ENL strongly transactivated several unrelated promoters including the promoter of Hoxa7 a potential target gene for the unaltered MLL protein. This transactivation capability was cell type specific and it was critically dependent on the contributions of the methyltransferase-homology (MT) region of MLL in combination with the C-terminus of ENL. Squelching experiments and gel retardation studies identified the ENL C-terminus as a binding partner for an unknown factor and the MLL MT region as a unique general DNA binding motif. The potential implications of these findings for the leukemogenesis by MLL-ENL are discussed.

Chemotherapy-related hepatotoxicity causing imaging findings resembling cirrhosis.

In this article, we describe three women in whom changes in the liver resembling cirrhosis occurred during systemic chemotherapy for metastatic breast carcinoma. All three patients were treated with tamoxifen as part of their chemotherapeutic regimen. Abnormalities of biochemical liver tests were associated with the development of a cirrhosis-like appearance of the liver on computed tomography. In two of the patients, hepatic metastases were proved at biopsy. The third patient had no radiologic evidence of metastatic disease. Chemotherapy for metastatic breast carcinoma may cause striking morphologic changes in the liver that resemble cirrhosis. Of importance, these changes should not be mistaken for the development or progression of liver metastases. Alternatively, because of the changes produced by chemotherapeutic agents, detection of metastases on computed tomography alone may be more difficult. Supplementary magnetic resonance imaging may be helpful in selected cases.