Mami Takanashi

Frequent co-expression of HoxA9 and Meis1 genes in infant acute lymphoblastic leukaemia with MLL rearrangement

Summary. We studied the expression of HoxA9 and Meis1 by reverse transcriptase‐polymerase chain reaction analysis in leukaemic cells from cases of infant acute lymphoblastic leukaemia (ALL, n = 27) and childhood ALL (n = 29). These two genes were co‐expressed significantly more frequently in infant ALL than in childhood ALL (19/27 vs0/29 cases, P < 0·001) and were highly associated with MLL gene rearrangement in infant ALL cases (P < 0·001). These findings indicate that the HoxA9 and Meis1 genes are closely associated with MLL gene rearrangement in the development of infant ALL, which represents a distinct entity of childhood ALL.

Expression of the Ikaros gene family in childhood acute lymphoblastic leukaemia

Summary. The Ikaros (Ik) gene family, which includes Ik, Aiolos (Ai), and Helios (He), is a primary regulator of lymphocyte differentiation, and is involved in the development of acute lymphoblastic leukaemia (ALL). We analysed the expression of the Ik gene family isoforms in 97 ALL cases, consisting of 64 childhood and 33 infant ALL cases, using reverse transcription‐polymerase chain reaction (RT‐PCR). Expression of Ik was detected in all cases, 87 of which expressed either Ik1 or Ik2, or both, five of which expressed Ik1/Ik2 and Ik6, and another five of which expressed only Ik6. Therefore, the dominant negative isoform of Ik6 was expressed in 10 of the 38 cases of childhood precursor B ALL, but was absent in other types of childhood ALL (26·3%, χ2‐test, P = 0·0001). In terms of Aiolos and Helios expression, 49 (65·3%) out of the 75 and 40 (50%) out of the 80 ALL cases tested showed non‐spliced Ai1 and He1 respectively. Only one case of T lineage ALL expressed a small‐sized isoform of Helios (designated as He6). It was also found that the expression of Ai1 and He1 was low in Ik6‐positive patients (Fishers exact test; Ai1 P = 0·005, Hel P = 0·035).

Ikaros dominant negative isoform (Ik6) induces IL-3-independent survival of murine pro-B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels

Ikaros is an essential regulator of lymphocyte differentiation. Mice transgenic for the Ikaros dominant negative (DN) mutation rapidly develop lymphoid malignancies. Various human leukemias have also been reported to express Ikaros DN isoforms, but its role in leukemogenesis is yet to be defined. We demonstrate that overexpressed Ikaros DN (Ik6) prolonged the survival of two different murine pro-B cell lines in cytokine deprived condition, and this was associated with increased expression of Bcl-xl. A survey of the upstream controller(s) of Bcl-xl expression revealed Ik6 overexpression enhanced the phosphorylation of JAK2 and STAT5. Interestingly, the Ik6 expressing cell lines showed reduced expression of B-cell differentiation surface marker CD45R (B220), which is also known as a JAK2 inhibitor. Although further evaluation with human clinical materials are required, these results propose a putative role of Ik6 in the development of B-lineage acute lymphoblastic leukemia, by activating the JAK2-STAT5 pathway and thus stimulating the production of Bcl-xl.

Diffuse bilateral thalamic astrocytomas as examined serially by MRI

Abstract We report the case of a 13-year-old girl with diffuse bilateral thalamic astrocytomas. Incoordination was observed at the onset. Cranial computed tomography (CT) showed enlarged thalami, and magnetic resonance imaging (MRI) revealed these lesions to be symmetrically enlarged with high intensity on the T2-weighted image. Owing to these atypical findings in the neuroimaging studies, we had difficulty in making the correct diagnosis of a brain tumor. After the diagnosis of diffuse bilateral thalamic astrocytomas was obtained, we performed hyperfractionated radiotherapy followed by chemotherapy. Radiation therapy was effective for a while, but the girls condition deteriorated again and she died 8 months after admission. Although diffuse bilateral thalamic astrocytomas are difficult to diagnose because they do not resemble most other neoplasms on neuroimaging studies, pediatricians should keep this entity in mind in order to arrive at a precise and prompt diagnosis.

Pneumatosis Cystoides Intestinalis with Abdominal Free Air in a 2-Year-Old Girl after Allogeneic Bone Marrow Transplantation

A 2-year-old girl with acute lymphoblastic leukemia (ALL) showing a t(4;11)(q21;q23) karyotype underwent allogeneic bone marrow transplantation (BMT) with the conditioning regimen of L-PAM (70 mg/m2/d for 3 days), busulfan (140 mg/m2/d for 2 days), and total body irradiation (12 Gy). On day 57, the patient developed pneumatosis cystoides intestinalis (PCI) when she received cyclosporin A and corticosteroids for graft-versus-host disease (GVHD). Because of the presence of massive abdominal free air and the suspicion of peritonitis, she underwent surgical intervention, which, however, revealed neither intestinal perforation nor peritoneal infection. She recovered from PCI in 10 days with nasogastric suction, fasting, and systemic broad-spectrum antibiotics. PCI with massive abdominal free air after BMT should be manageable by conservative therapy alone.

Early blastic transformation following complete cytogenetic response in a pediatric chronic myeloid leukemia patient treated with imatinib mesylate.

This article reports early blastic transformation of chronic myeloid leukemia (CML) in a child following a complete cytogenetic response induced by imatinib mesylate. A 14-year-old Japanese boy was diagnosed with t(9;22) cryptic CML in the chronic phase and treated with imatinib. His response to treatment was slow, but a major cytogenetic response was obtained at 142 days of therapy. However, he developed lymphoid blastic transformation at 9 months. He attained remission with acute lymphoblastic leukemia-type chemotherapy and then successfully received a non-T-cell-depleted allogeneic stem cell transplantation (allo-SCT) with his mothers two loci-mismatched donor cells. A sudden blastic transformation may occur even with a complete cytogenetic response induced by imatinib. CML patients who respond slowly to imatinib may still be candidates for allo-SCT, even when a major cytogenetic response is obtained.

Hemophagocytic lymphohistiocytosis during maintenance treatment of precursor B-cell acute lymphoblastic leukemia.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but occasionally life-threatening disorder. HLH is characterized by hypercytokinemia induced by activated T-cells and macrophages, resulting in hemophagocytosis in bone marrow and other reticuloendothelial systems. Prompt diagnosis and the implementation of appropriate therapy are mandatory; otherwise this uncontrolled hypersecretion of inflammatory cytokines leads to the hyperactivation of macrophages, hypercoagulability and bone marrow suppression, resulting in multiple-organ failure [1]. The development of HLH is thought to be quite rare in patients with acute lymphoblastic leukemia (ALL) [2]. In a Japanese nationwide survey, among 567 patients diagnosed with HLH over the last 5 years it was clarified that only 3 patients with ALL (0.5%) and 9 patients with AML (1.5%) developed HLH [3]. Herein, we report a case of HLH associated with an infection that was caused by an unidentified pathogen during the maintenance phase of precursor B-cell ALL; this patient was successfully treated with immunochemotherapy including etoposide. A 2-year-old boy was admitted to our hospital with a complaint of fever. He had previously been healthy, and there was no family history of particular note. Bone marrow aspiration showed proliferation of lymphoid cells which