Clinical value of RAG1 expression and IKZF1 deletions in Philadelphia negative pediatric B cell precursor acute lymphoblastic leukemia

Abstract

This study aimed to address the clinical impact of recombination-activating gene (RAG1) expression and tumor suppressor IKZF1 gene deletions in Philadelphia negative B-cell precursor acute lymphoblastic leukemia (B-ALL) patients. Fifty newly diagnosed pediatric Philadelphia negative B-ALL patients were included in this study. Using Bone Marrow samples, RAG1 expression was assessed by real time PCR and IKZF1 deletions were determined by multiplex real-time quantitative PCR. The expression of RAG1 was significantly higher in B-ALL patients as compared to the controls (p?<?.001). The B-ALL patients with RAG1 high expression (≥median) had lower response to induction of remission, shorter DFS, shorter overall survival, higher blast cells, and white cell counts in the peripheral blood as compared to those with low RAG1 expression levels (p?<?.01 for all). Likewise, there was significant association between IKZF1 deletion and high RAG1 expression. Based on our findings RAG1 high expression and IKZF1 deletions were associated with adverse prognosis in Philadelphia negative B-ALL. RAG1 could be used as therapeutic target in the treatment of B-ALL.     

IFR4/MUM1‐positive lymphoma in Waldeyer ring with co‐expression of CD5 and CD10

IRF4/MUM1‐positive lymphoma is a new subgroup of germinal center‐derived B‐cell lymphoma, predominantly involving the Waldeyer ring (WR) in children. CD5 expression is rare in these lymphomas. We report a 7‐year‐old Chinese male with B‐cell lymphoma. Evaluation of his specimen by morphology, immunohistochemistry, and FISH analysis demonstrated IRF4/MUM1‐positive lymphoma with strong and extensive CD5 and CD10 positivity. Despite the lack of t(14;18)(q32;q21) rearrangement, BCL2 protein was expressed. Our report highlights the clinicopathologic features of IFR4/MUM1‐positive lymphoma in WR with co‐expression of CD5 and CD10, and thereby provides insight into this newly recognized disease entity.     

Clinical,histologic, and genetic features of mesothelioma in a 7‐Year‐old child

Malignant mesothelioma (MM) is a highly aggressive malignancy that is extremely rare in children. This case report documents a 7‐year‐old male without previous asbestos exposure with peritoneal MM that initially responded to chemotherapy with cisplatin and gemcitabine but ultimately metastasized to his chest. He was diagnosed with MM based on histology, extensive immunohistochemical analyses, and an elevated serum CA‐125 level. Cytogenetics and comparative genomic hybridization (CGH) analysis of his tumor identified a single extra copy number of chromosome 11 with few other changes noted. Pediatr Blood Cancer 2013; 60: 146–148. © 2012 Wiley Periodicals, Inc.     

Decreased expression of β1 integrin in enteric neural crest cells of the endothelin receptor B null mouse model

Interactions between enteric neural crest-derived cells (ENCC) and the surrounding intestinal microenvironment, such as the extracellular matrix (ECM), are critical for regulating enteric nervous system (ENS) development. Integrins are the major receptors for ECM molecules, such as laminin, which have been reported to be involved in the pathogenesis of Hirschsprung’s disease. In this study, we examined the expression of β1 integrin in the endothelin receptor B (Ednrb) knock out (KO) mouse gut, which presents with an aganglionic colon. A Sox10-Venus-positive Ednrb KO mouse, where ENCC is labeled with fluorescent protein, ‘Venus’, was created. Sox10-Venus-positive Ednrb wild type (WT) were used as controls. Small intestine, proximal colon and distal colon were dissected on E13.5 and E15.5 and β1 integrin expression of the gut tissue was examined by immunohistochemistry and real time RT-PCR. The cells of the gut dissected on E11.5 were isolated and cultured for 2 days. Venus-positive ENCC were immunostained with β1 integrin and Tuj-1, which is a marker for neurons. The expression of β1 integrin was not significantly different between KO and WT in all parts of the gut examined. However, the β1 integrin expression in the isolated ENCC was significantly decreased in KO compared to WT. The average threshold area was 42.98 ± 17.47% in KO and 73.53 ± 13.77 in WT (p < 0.001). We demonstrated that β1 integrin expression was specifically decreased in ENCC in Ednrb KO mice. Our results suggest that impaired interaction between integrin and its ligands may disturb normal ENS development, resulting in an aganglionic colon.     

DNAJB1‐PRKACA–positive metastatic fibrolamellar carcinoma with unknown primary in a pediatric patient

Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma, occurring in children and young adults without underlying liver disease. The diagnosis is based on morphological characteristics of the tumor, supplemented by immunohistochemistry and/or genetic testing. Recently, the presence of a characteristic DNAJB1‐PRKACA fusion gene has been associated with FLC. Herein, we report a case of FLC presenting as peritoneal carcinomatosis in a 14‐year‐old female. Interestingly, no liver tumor was seen on imaging, and an alternative possibility is that the tumor arose outside the liver as a hepatoid carcinoma with fibrolamellar features.     

Influence of open testicular biopsy in prepubertal rats on rats' adulthood fertility with correlation to serum levels of inhibin B and follicle stimulating hormone

ObjectiveOpen testicular biopsy (OTB) is one of the options to accurately assess fertility potential of the undescended testis. The aim of the study was to investigate consequences of OTB in prepubertal rats on their adulthood fertility.MethodsThirty-eight prepubertal male rats were divided into three groups depending on day 20 procedure. The first group was the control group, the second sham operated and the third has left OTB. Bilateral orchiectomy was performed on day 70 to all groups, with determination of serum inhibin B and follicle stimulating hormone (FSH). Removed testes were compared according to the weight, volume, spermatogenesis, histological and apoptotic changes in both testes with differences in serum levels of inhibin B and FSH.ResultsIpsilateral testicular weight, volume, and spermatogenesis reduction with a reduction of tubular number, diameter and germinative epithelium was found in OTB group. Significant increase in apoptotic index was found in biopsied testis without compensatory hypertrophy of contralateral testis. Differences of inhibin B and FSH were not statistically significant among three groups.ConclusionOTB in prepubertal rats has detrimental effects on fertility in adulthood. It does not cause compensatory hypertrophy of the contralateral testis nor does it disturb serum levels of inhibin B and FSH.     

Spermatogenic defects in F2 mice between normal mouse strains C3H and C57BL/6 without mutation

Genetic disorders are usually considered to be caused by harmful gene mutations, as well as by chromosomal aberrations, including small insertions, duplications and/or deletions. However, as infertile individuals often arise among the offspring of crosses between two fertile mouse strains, we postulate that a certain combination of ‘normal’ genes with neither gene mutations nor chromosomal aberrations can cause such serious phenotypic alterations as reproductive dysfunction. In this study, we show evidence that a combination of multiple normal genes from two different normal mouse strains manifests a wide range of male reproductive dysfunctions, from benign changes to complete infertility. These abnormal phenotypes are thought to have occurred by epistatic interactions of alleles.