Papers - MORITAKE Hiroshi
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A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia Reviewed
Honda Y., Muramatsu H., Nanjo Y., Hirabayashi S., Meguro T., Yoshida N., Kakuda H., Ozono S., Wakamatsu M., Moritake H., Yasui M., Sano H., Manabe A., Sakashita K.
International Journal of Hematology 115 ( 2 ) 263 - 268 2022.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology
Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III–IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.
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Nagasawa S., Yamada A., Kinoshita M., Kamimura S., Moritake H.
Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e14970 2022.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatrics international : official journal of the Japan Pediatric Society
DOI： 10.1111/ped.14970
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Kinoshita M., Yamada A., Saito Y., Kamimura S., Moritake H.
Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e14975 2022.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatrics international : official journal of the Japan Pediatric Society
DOI： 10.1111/ped.14975
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Matsuyama Misayo, Sawada Hirotake, Inoue Shinobu, Hishinuma Akira, Sekiya Ryo, Sato Yuichiro, Moritake Hiroshi
Clinical Pediatric Endocrinology 31 ( 3 ) 185 - 191 2022
Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Pediatric Endocrinology
<p>Thyroglobulin gene abnormalities cause thyroid dyshormonogenesis. A 6-yr-old boy of consanguineous parents presented with a large goiter and mild hypothyroidism (thyroid-stimulating hormone [TSH] 7.2 μIU/mL, free T3 [FT3] 3.4 pg/mL, free T4 [FT4] 0.6 ng/dL). Despite levothyroxine (LT4) administration and normal TSH levels, the goiter progressed slowly and increased rapidly in size at the onset of puberty. Thyroid scintigraphy revealed a remarkably high <sup>123</sup>I uptake of 75.2%, with a serum thyroglobulin level of 13 ng/ml, which was disproportionately low for the goiter size. DNA sequencing revealed a novel homozygous missense variant, c.434G>A [p.Gly145Glu], in the thyroglobulin gene. Goiter growth was suppressed by increasing the LT4 dose. Thyroidectomy was performed at 17-yr-of-age. Thyroglobulin analysis of the thyroid tissue detected mutant thyroglobulin present in the endoplasmic reticulum, demonstrating that thyroglobulin transport from the endoplasmic reticulum to the Golgi apparatus was impaired by the Gly145Glu variant. During the clinical course, an elevated FT3/FT4 ratio was observed along with thyroid enlargement. A high FT3/FT4 ratio and goiter seemed to be compensatory responses to impaired hormone synthesis. Thyroglobulin defects with goiter should be treated with LT4, even if TSH levels are normal.</p>
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集学的治療が有効であった顎下部原発滑膜肉腫 Reviewed
中川 緑,山田 愛,木下 真理子,齋藤 祐介,上村 幸代,石原 明,陣内 崇,楠原 和朗,小田 義直,盛武 浩
宮崎会医師会医学会誌 46 46 - 50 2022
Language：Japanese Publishing type：Research paper (scientific journal)
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妊娠中のポリフェノール含有飲食物の常習的摂取が原因と考えられた胎児動脈管早期収縮 Reviewed
楯真由美,黒木亜津子,山下 尚人,原田 雅子,盛武 浩
宮崎会医師会医学会誌 46 38 - 41 2022
Language：Japanese Publishing type：Research paper (scientific journal)
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ヒト脳脊髄液中topotecan濃度のHPLC分析法構築と髄腔内薬物投与後の排泄評価 Reviewed
吉川 直樹, 山田 愛, 横田 翼, 山田 侑世, 木下 真理子, 盛武 浩, 池田 龍二
日本臨床薬理学会学術総会抄録集 43 ( 0 ) 3-C-P-110 2022
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本臨床薬理学会
【目的】抗悪性腫瘍薬の髄腔内投与は、髄液中の薬物濃度を高く維持し、全身性の副作用が最小化される利点を有する。しかし、脳室内薬物のクリアランスは全ての患者で一律ではない。従って、安全な抗悪性腫瘍薬の髄腔内投与のためには、局所薬物動態を評価可能な環境が必要である。髄腔内投与後の髄液中薬物濃度が評価できれば、患者ごとに適切な用法・用量での化学療法が可能となる。Topoisomerase I阻害剤topotecanは、横紋筋肉腫、髄芽腫、神経芽腫などの小児腫瘍の治療に使用され、その有効性が認識されてきている。髄腔内投与後の髄液中topotecan濃度の評価は第I相臨床試験に限定され、髄液中topotecan濃度モニタリングに基づく個別化医療については未だ議論されていない。そこで本研究では、HPLCを使用した簡便かつ再現性の高い髄液中topotecan濃度測定法を開発し、その臨床応用性を確認した。【方法】脳脊髄液中topotecan濃度を測定するためのHPLC法には、Prominence UFLCシステムおよびC18カラムを使用した。Topotecanは生理的条件下にてラクトン環が閉環したラクトン型と開環したカルボキシレート型が可逆的に平衡状態で存在する。本法では総topotecan濃度を定量するために、分析対象試料のラクトン環の状態をpH調整処理により制御した後、除蛋白処理を施した。Topotecanは蛍光検出により定量した（励起波長380 nm、発光波長520 nm）。さらに、topotecan髄腔内投与中の1歳児より脳脊髄液を採取し、本法にて脳脊髄液中topotecan濃度をモニタリングした。【結果・考察】脳脊髄液中topotecanは試料調製時のシンプルなpH調整により、閉環型および開環型への変換が確認された。この2形態は構築した分析法により明確に分離することができ、開環型と閉環型の保持時間はそれぞれ1.3分と3.2分であった。髄液が吸収不良により停滞する患者にトポテカンを髄腔内投与後、本法を用いて、投与24、48、72時間後の脳脊髄液中topotecan濃度をモニタリングした。投与24、48時間後において、投与量を反映した脳脊髄液中濃度の定量に成功した。従って本法は、髄腔内投与後のtopotecan排泄遅延を検出可能と考える。【結論】日常的なtopotecanモニタリングを実現することで、topotecanの髄腔内投与における投与量および投与間隔の適時調整が可能となった。本研究成果は、抗悪性腫瘍薬の髄腔内投与における個別化治療法の実現に貢献するものである。
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Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia Reviewed
Saito Y., Kinoshita M., Yamada A., Kawano S., Liu H.S., Kamimura S., Nakagawa M., Nagasawa S., Taguchi T., Yamada S., Moritake H.
Cancer Science 112 ( 12 ) 4944 - 4956 2021.12
Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Cancer Science
Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.
DOI： 10.1111/cas.15138
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Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case. Reviewed
Baba T, Kawano T, Saito Y, Onishi S, Yamada K, Yamada W, Masuya R, Nakame K, Kawasaki Y, Iino S, Sakoda M, Kirishima M, Kaji T, Tanimoto A, Natsugoe S, Ohtsuka T, Moritake H, Ieiri S
Surgical case reports 7 ( 1 ) 212 2021.9
Language：English Publishing type：Research paper (scientific journal)
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Taga T., Tanaka S., Hasegawa D., Terui K., Toki T., Iwamoto S., Hiramatsu H., Miyamura T., Hashii Y., Moritake H., Nakayama H., Takahashi H., Shimada A., Taki T., Ito E., Hama A., Ito M., Koh K., Hasegawa D., Saito A.M., Adachi S., Tomizawa D.
Leukemia 35 ( 9 ) 2508 - 2516 2021.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Leukemia
Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 95.0% and 96.7% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 98.1% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD with EFS were 14.67 (p = 0.01). Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.
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Yoshikawa N., Yamada A., Yokota T., Yamada Y., Kinoshita M., Moritake H., Ikeda R.
Cancers 13 ( 18 ) 2021.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Cancers
Intrathecal administration of anticancer drugs is an effective dosage strategy, but the elimination of intraventricular drugs is not uniform in all patients. For safety, a system to evaluate local pharmacokinetics in the ventricles after administration is desired. In this study, we developed a simple and reproducible method to measure topotecan concentration in the cerebrospinal fluid (CSF) and confirmed its clinical applicability. High-performance liquid chromatography (HPLC) analysis was performed using a C18 column to measure the total topotecan concentration in the CSF. Clinical CSF samples were obtained from a 1-year old child with poor CSF absorption and stagnation. The patient received topotecan via an intraventricular subcutaneous reservoir. The HPLC method complied with the validation criteria. The lower limit of quantitation of this method was 0.04 µM. Using the developed method, we could determine the difference in topotecan CSF concentrations at 24 and 48 h after administration. The patient’s topotecan elimination rate was extremely low, and signs of adverse effects were observed at high CSF concentration of topotecan. The developed method could detect the delay in topotecan elimination after intrathecal injection. The findings of this study are valuable for the development of personalized treatments for the intrathecal administration of anticancer drugs.
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Azuma M., Kadota Y., Matsuyama M., Moritake H., Hirai T.
Japanese Journal of Radiology 39 ( 6 ) 564 - 570 2021.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Radiology
Objective: We evaluated the usefulness of fat-suppressed three-dimensional T1-weighted volume isotropic turbo spin-echo acquisition (FS 3D T1W-VISTA) imaging for the evaluation of the ectopic posterior pituitary gland (EPPG). Materials and methods: This retrospective study included 9 patients with EPPG due to causes other than tumor. All underwent sagittal two-dimensional (2D) T1W-, FS 3D T1W-VISTA- (VISTA), and 3D T2W-driven equilibrium radiofrequency reset pulse (DRIVE) imaging. Two radiologists independently reviewed the 2D T1W- and VISTA images for their image quality and for visualization of the EPPG and of pituitary stalk transection. DRIVE findings were used as the reference standard for pituitary stalk transection. Interobserver and intermodality agreements were evaluated with the kappa (κ) coefficient. The mean grade assigned to the 2D T1W- and the VISTA imaging technique for visualization of the EPPG was assessed by the Mann–Whitney U test. Results: Interobserver agreement for visualization of the EPPG on 2D T1W- and VISTA images was excellent (κ = 0.82 and κ = 1.00, respectively). The mean grade for EPPG visualization was significantly higher for VISTA- than 2D T1W images (p = 0.0039). Conclusion: FS 3D T1W-VISTA imaging is useful for the evaluation of EPPG. A secondary abstract: Conventional MRI yields insufficient information for the evaluation of the ectopic posterior pituitary gland (EPPG). The visualization of the EPPG was significantly higher for fat-suppressed three-dimensional T1-weighted volume isotropic turbo spin-echo acquisition (FS 3D T1W-VISTA) than 2D T1W images. FS 3D T1W-VISTA imaging is useful for the evaluation of the EPPG.
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Aoki T., Takahashi H., Tanaka S., Shiba N., Hasegawa D., Iwamoto S., Terui K., Moritake H., Nakayama H., Shimada A., Koh K., Goto H., Kosaka Y., Saito A.M., Horibe K., Kinoshita A., Tawa A., Taga T., Adachi S., Tomizawa D.
British Journal of Haematology 193 ( 1 ) 176 - 180 2021.4
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：British Journal of Haematology
The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.
DOI： 10.1111/bjh.16656
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Yoshikawa N., Yamada A., Yokota T., Moritake H., Hirabara Y., Ikeda R.
Journal of Clinical Laboratory Analysis 35 ( 3 ) e23661 2021.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Laboratory Analysis
Background: The concentration of MTX in blood is often measured quickly and easily by immunoassays. Thus, immunoassays may facilitate the easy determination of the concentration of MTX in the cerebrospinal fluid (CSF). In this study, we measured methotrexate (MTX) concentrations in the CSF using a high-performance liquid chromatography (HPLC) method intended for analyzing CSF matrices and a chemiluminescence immunoassay (CLIA) method intended for assessing serum and plasma matrices and verified the differences in the results of the two methods. Methods: HPLC analysis for MTX in the CSF was performed using a Prominence UFLC system with a C18 column. The HPLC method was validated in accordance with the 2018 FDA guideline. The CLIA method was performed using an ARCHITECT i1000SR system intended for serum and plasma matrices. A total of 47 CSF samples (14 clinical and 33 spiked specimens) were analyzed using the two methods. Results: The HPLC method passed the validation criteria. The concentration of MTX in the same sample, determined using the HPLC and CLIA methods, differed proportionally; the percent difference in the concentrations averaged −23.0% (95% confidence interval: −36.9% to −9.1%) as revealed by the Bland-Altman plot. The relationship between the measured values, evaluated using the Passing-Bablok regression, was as follows: HPLC = 1.205 × CLIA – 0.024. Conclusion: The equation deduced in this study can be used to correct the concentration of MTX measured using the CLIA method.
DOI： 10.1002/jcla.23661
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A useful method to diagnose Pearson syndrome mimicking Diamond–Blackfan anemia Reviewed
Nishimura T., Yamada A., Utoyama M., Saito Y., Moritake H.
Pediatrics International 63 ( 2 ) 223 - 225 2021.2
Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatrics International
DOI： 10.1111/ped.14385
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Moritake H., Tanaka S., Miyamura T., Nakayama H., Shiba N., Shimada A., Terui K., Yuza Y., Koh K., Goto H., Kakuda H., Saito A., Hasegawa D., Iwamoto S., Taga T., Adachi S., Tomizawa D.
Pediatric Blood and Cancer 68 ( 1 ) e28736 2021.1
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatric Blood and Cancer
Background: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. Procedure: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. Results: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P <.01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P <.01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P <.01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P =.04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P <.01). Conclusions: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.
DOI： 10.1002/pbc.28736
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Hasegawa D., Tawa A., Tomizawa D., Watanabe T., Saito A.M., Kudo K., Taga T., Iwamoto S., Shimada A., Terui K., Moritake H., Kinoshita A., Takahashi H., Nakayama H., Koh K., Goto H., Kosaka Y., Miyachi H., Horibe K., Nakahata T., Adachi S.
Pediatric Blood and Cancer 67 ( 12 ) e28692 2020.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatric Blood and Cancer
We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P =.16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P =.060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.
DOI： 10.1002/pbc.28692
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Prevention of cisplatin-induced hearing-loss by sodium thiosulfate in medulloblastoma Reviewed
Harao T, Yamada A, Kinoshita M, Kamimura S, Moritake H
62 ( 10 ) 1204 - 1206 2020.9
Authorship：Lead author, Last author Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1111/ped.14271
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Temozolomide and etoposide combination for the treatment of relapsed osteosarcoma Reviewed
Akazawa R., Umeda K., Saida S., Kato I., Hiramatsu H., Sakamoto A., Arakawa Y., Sumiyoshi S., Okamoto T., Moritake H., Adachi S., Takita J.
Japanese Journal of Clinical Oncology 50 ( 8 ) 948 - 952 2020.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Clinical Oncology
The prognosis of patients with relapsed osteosarcoma is extremely poor and the optimal treatment remains to be identified. Here, we retrospectively analysed the clinical outcomes of nine patients with relapsed osteosarcoma treated with temozolomide/etoposide. Of the two patients who received temozolomide/etoposide as palliative therapy for unresectable tumours, one remained alive with stable disease for >4 years. The remaining seven patients received temozolomide/etoposide as adjuvant therapy following resection of relapsed metastatic disease; of these, one was free from disease for 41 months. Potentially beneficial effects were observed in two of three O6-methylguanine-DNA methyltransferase protein-negative patients, whereas all five O6-methylguanine-DNA methyltransferase-positive patients experienced subsequent relapse. None of the patients experienced severe adverse effects requiring hospitalization. Temozolomide/etoposide is a feasible candidate as salvage therapy for relapsed osteosarcoma. Further studies are needed to verify the utility of O6-methylguanine-DNA methyltransferase protein expression as a biomarker for predicting the response to this treatment.
DOI： 10.1093/jjco/hyaa070
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Terui K., Toki T., Taga T., Iwamoto S., Miyamura T., Hasegawa D., Moritake H., Hama A., Nakashima K., Kanezaki R., Kudo K., Saito A.M., Horibe K., Adachi S., Tomizawa D., Ito E.
Genes Chromosomes and Cancer 59 ( 3 ) 160 - 167 2020.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Genes Chromosomes and Cancer
Myeloid leukemia associated with Down syndrome (ML-DS) is characterized by a predominance of acute megakaryoblastic leukemia, the presence of GATA1 mutations and a favorable outcome. Because DS children can also develop conventional acute myeloid leukemia with unfavorable outcome, detection of GATA1 mutations is important for diagnosis of ML-DS. However, myelofibrosis and the significant frequency of dry taps have hampered practical screening of GATA1 mutations using bone marrow (BM) samples. In response to those problems, 82 patients were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D11 study. GATA1 mutations were analyzed by Sanger sequencing (SS) using genomic DNA (gDNA) from BM and cDNA from peripheral blood (PB) followed by targeted next-generation sequencing (NGS) using pooled diagnostic samples. BM and PB samples were obtained from 71 (87%) and 82 (100%) patients, respectively. GATA1 mutations were detected in 46 (56%) and 58 (71%) patients by SS using BM gDNA and PB cDNA, respectively. Collectively, GATA1 mutations were identified in 73/82 (89%) patients by SS. Targeted NGS detected GATA1 mutations in 74/82 (90%) patients. Finally, combining the results of SS with those of targeted NGS, GATA1 mutations were identified in 80/82 (98%) patients. These results indicate that SS using BM gDNA and PB cDNA is a rapid and useful method for screening for GATA1 mutations in ML-DS patients. Thus, a combination of SS and targeted NGS is a sensitive and useful method to evaluate the actual incidence and clinical significance of GATA1 mutations in ML-DS patients.
DOI： 10.1002/gcc.22816