Biomedical subjects

Yuka Harada

Publications and source records attributed to Yuka Harada.

7 recordsLinked to original sources

PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗

PubMed2006

Nuclear abnormalities in aspirated thyroid cells and chromosome aberrations in lymphocytes of residents near the Semipalatinsk nuclear test site.

Chromosomal studies in peripheral lymphocytes from 63 residents near the Semipalatinsk nuclear test site, at ages of 52-63 years old, were performed in 2001-2002. A higher rate of chromosome aberrations was observed in the two contaminated villages, Dolon and Sarjal, compared with the control village, Kokpekti. Moreover, a relationship of frequency of cells with radiation induced chromosome aberrations and the previously estimated exposure dose was observed. Furthermore, apparent nuclear abnormalities (ANA) of thyroid follicular cells were studied in 30 out of 63 residents, who were examined for chromosome aberrations. A higher rate of ANA was also found in the residents in the exposed villages compared with those in the control village. These results suggest radiation effects both on the chromosomes in peripheral lymphocytes and on the follicular cells in the thyroid.

Adolescent↗

PubMed2006

Implications of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome (MDS): future molecular therapeutic directions for MDS.

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. MDS is also a susceptibility to acute myeloid leukemia (AML) and shown to be extremely resistant to current therapeutic strategies. MDS in a subset of 10-20% of patients arise after previous chemotherapy or radiation exposure for other malignancies. Because MDS is a heterogeneous disorder, specific gene abnormalities playing a role in the myelodysplastic process have been difficult to identify. Cytogenetic abnormalities are seen in half of MDS patients, and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Genes more frequently implicated in the pathogenesis of MDS remain unknown. Although point mutations of critical genes have been demonstrated to contribute to the development MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene, which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of AML, in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt) and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most of AML1/RUNX1 mutants lose trans-activation potential, which leads to a loss of AML1 function indicating that AML1/RUNX1 dysfunction is one of the major pathogenesis of MDS/AML. Normalizing AML1 function or regulating cooperative gene mutations would provide an important clue for molecular target therapies.

Animals↗

PubMed2005

Point mutations in the AML1/RUNX1 gene associated with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. Because MDS is a heterogeneous disorder, specific gene abnormalities implicated in the pathogenesis of MDS have been difficult to identify. Cytogenetic abnormalities are seen in half of the MDS patients and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Although point mutations of critical genes had been demonstrated to contribute to the development of MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene (which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of acute myeloid leukemia [AML]) in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lose trans-activation potential, which leads to a loss of AML1 function. These data indicate that AML1 point mutation is one of the major causes of MDS/AML, and "MDS/AML with AML1 mutation" represents a distinct clinicopathologic-genetic entity.

Acute Disease↗

PubMed2003

High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia.

A high incidence of somatically acquired point mutations in the AML1/RUNX1 gene has been reported in poorly differentiated acute myeloid leukemia (AML, M0) and in radiation-associated and therapy-related myelodysplastic syndrome (MDS) or AML. The vast majority of AML1 mutations identified in these diseases were localized in the amino (N)-terminal region, especially in the DNA-binding Runt homology domain. In this report, we show that AML1 point mutations were found in 26 (23.6%) of 110 patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined these 3 disease categories as MDS/AML). Among them, 9 (8.2%) mutations occurred in the carboxy (C)-terminal region, which were exclusively found in MDS/AML and were strongly correlated with sporadic MDS/AML. All patients with MDS/AML with an AML1 mutation expressed wild-type AML1 protein and had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lost trans-activation potential, regardless of their DNA binding potential. These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopathologic-genetic entity.

Adult↗

PubMed2002

Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia.

Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and down-regulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors.

Acute Disease↗

PubMed2002

Nationwide study of idiopathic thrombocytopenic purpura in pregnant women and the clinical influence on neonates.

Idiopathic thrombocytopenic purpura (ITP) occurs more commonly in young women during the reproductive years. To obtain information for management of ITP in pregnancy, we performed a nationwide retrospective survey. Findings from a total of 284 pregnant women with ITP and their 286 newborn infants were available for analysis. The bleeding tendency at delivery was managed chiefly with corticosteroid, intravenous high-dose gamma-globulin, and platelet transfusion. Maternal complications occurred in 77 cases (27.1%) and were frequently seen in cases with poor control of ITP. Neonatal abnormalities, which were not influenced by the clinical state of the mother, occurred at a frequency of 17.8%. Thrombocytopenia in neonates occurred in 48 cases (22.4%), and bleeding tendency was found in 16 cases (6.3%) without severe bleeding. Prediction of thrombocytopenia in neonates was difficult. However, infants from splenectomized mothers with well-controlled ITP showed thrombocytopenia more frequently than those from nonsplenectomized mothers. Mothers treated with steroids at doses greater than 15 mg/day showed a high frequency of maternal complications and fetal abnormal body weight. These observations will be useful in the management of pregnant women with ITP and their infants.

Abnormalities, Drug-Induced↗