Akihiro Nakajima

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells : Involvement of ATM-dependent DNA damage response pathways

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 μM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21CIP1 and p27KIP1. These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

Telomerase inhibition enhances apoptosis in human acute leukemia cells : possibility of antitelomerase therapy

Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. We examined the impact of telomerase inhibition by the dominant-negative human catalytic subunit of telomerase (DN-hTERT) on the biological features of acute leukemia. We introduced vectors encoding dominant- negative (DN)-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistant marker into a telomerase-positive human acute lymphoblastic leukemia cell line, HAL-01. Expression of DN-hTERT dramatically inhibited telomerase activity, leading to apoptotic cell death. Mutant telomerase expression also enhanced daunorubicin-induced apoptosis. Nude mice (n=5 per group) received subcutanous implants of HAL-01 cells expressing the control vector or DN-hTERT or WT-hTERT. Implantation of HAL-01 cells expressing control vector (n=5) rapidly produced tumors, whereas implantation of those expressing DN-hTERT (n=5) did not. Thus, telomerase inhibition both growth of HAL-01 cells in vitro and tumorigenic capacity in vivo. Furthermore, the G-quadruplex-interactive telomerase-specific inhibitor, telomestatin, shortened the telomere length and induced apoptosis in freshly isolated primary acute leukemia cells. These results suggest that antitelomerase therapy may be useful in some acute leukemias in combination with antileukemic agents such as daunorubicin.

Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis.

Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis

ABL-specific tyrosine kinase inhibitor, STI571 in vitro , affects Ph-positive acute lymphoblastic leukemia and chronic myelogenous leukemia in blastic crisis

ABL-specific tyrosine kinase inhibitor, STI571 in vitro , affects Ph-positive acute lymphoblastic leukemia and chronic myelogenous leukemia in blastic crisis

Myeloid/Natural Killer Cell Precursor Acute Leukemia Accompanied by Homozygous Protein C Deficiency

A patient with myeloid/natural killer (NK) cell precursor acute leukemia who was also homozygous for protein C deficiency was treated and showed a complete remission while he simultaneously received low molecular weight heparin. He presented with fever spikes, lymphadenopathy, and a bulky tumor of the anterior mediastinum.A bone marrow aspirate showed the infiltration of immature lymphoblastoid cells. The patient’s diagnosis was determined to be myeloid/NK cell precursor acute leukemia by morphologic and immunophenotypic analysis (CD7+CD33+CD34+CD56+). The patient developed a thrombosis in his jugular vein on cannulation of the internal jugular vein. An examination of the serum levels and the activities of proteins C and S demonstrated a slight decrease in the protein C level but an undetectable protein C activity.The patient received the diagnosis of homozygous protein C deficiency, because both parents were found to have heterozygous protein C activity. Treatment of the patient’s leukemia included induction chemotherapy (Ara-C and idarubicin) with concomitant administration of low molecular weight heparin for his homozygous protein C deficiency. He achieved a complete remission without expressing any thrombosis during the course of chemotherapy.To our knowledge, this is the first case ever described in which acute myeloid leukemia was complicated with homozygous protein C deficiency. Int J Hematol. 2003;78:149-153.

Multiple myeloma with monosomy 13 developed in trisomy 13 acute myelocytic leukemia: numerical chromosome abnormality during chromosomal segregation process

We report here an acute myelocytic leukemia (AML-M2) patient with trisomy 13 as the sole cytogenetic anomaly, who had relapse of AML with a normal karyotype and developed multiple myeloma. Fluorescence in situ hybridization analysis using the RB gene probe revealed the plasma cells of multiple myeloma (MM) to have monosomy 13 anomaly, whereas relapsed blast cells of AML carried disomy of chromosome 13. To our knowledge, this is the first case showing clonal evolution of trisomy 13 AML and monosomy 13 MM, which might be derived from the leukemic clone at relapse.

ABL gene fuses BCR during t(20;22) results in Philadelphia-negative, but BCR/ABL-positive chronic myeloid leukemia

ABL gene fuses BCR during t(20;22) results in Philadelphia-negative, but BCR/ABL-positive chronic myeloid leukemia