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Long-term follow-up of efficacy and safety in elderly patients with chronic myeloid leukemia treated with intermittent low dose dasatinib therapy 对接受间歇性小剂量达沙替尼治疗的老年慢性髓性白血病患者的疗效和安全性进行长期随访
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100452
Masahiro Imamura , Yusuke Nakamura , Daisuke Hidaka , Reiki Ogasawara , Kohei Okada , Junichi Sugita , Shuichi Ota

Intermittent low dose dasatinib therapy brought about a beneficial effect in elderly patients with chronic-phase chronic myeloid leukemia (CML-CP) without inducing severe adverse events (AEs). An 85-year-old male patient, who received twice-weekly, thrice-weekly, or four-times-weekly administration of 20 mg/day dasatinib after once-weekly administration, achieved a major molecular response two years after the start of dasatinib treatment and later sometimes achieved a deep molecular response, maintaining the efficacy for 11 years. The mean daily dose ranged from 5.7 mg to 11.4 mg. Furthermore, a 79-year-old male patient, who received thrice-weekly or every other day administration of 20 mg/day dasatinib after once-weekly administration, achieved a deep molecular response at four and half years after the start of dasatinib treatment. The mean daily dose is 8.6 mg. Intermittent low dose dasatinib therapy appears to be feasible in elderly patients with CML-CP. The goal of treatment in elderly patients with CML-CP appears to be different from that in younger patients, since they often suffer from serious AEs in the case of standard dose tyrosine kinase inhibitor therapy, followed by the dose reduction or cessation of treatment.

间歇性小剂量达沙替尼治疗为老年慢性髓性白血病(CML-CP)患者带来了有益的疗效,且不会诱发严重的不良反应(AEs)。一名85岁的男性患者在接受每周一次、每周三次或每周四次、每次20毫克/天的达沙替尼治疗后,在开始达沙替尼治疗两年后获得了主要分子反应,后来有时又获得了深度分子反应,疗效维持了11年。平均每日剂量从 5.7 毫克到 11.4 毫克不等。此外,一名 79 岁的男性患者在每周服用达沙替尼一次后,又接受了每周三次或隔日服用 20 毫克/天的达沙替尼治疗,并在开始达沙替尼治疗四年半后获得了深度分子反应。平均日剂量为 8.6 毫克。间歇性低剂量达沙替尼治疗在老年 CML-CP 患者中似乎是可行的。老年CML-CP患者的治疗目标似乎与年轻患者不同,因为他们在接受标准剂量酪氨酸激酶抑制剂治疗时常常会出现严重的AE,随后会减少剂量或停止治疗。
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引用次数: 0
Diagnostic challenges in classification of plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia in the context of secondary-type mutations 与急性髓性白血病相关的浆细胞树突状细胞增殖在次生型突变背景下的分类诊断难题
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100480
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引用次数: 0
Acute myeloid leukemia with a ZMYND11::MBTD1 fusion gene following chemotherapy and radiotherapy for breast cancer: A case report 乳腺癌化疗和放疗后出现 ZMYND11::MBTD1 融合基因的急性髓性白血病:病例报告
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100478

The t(10;17)(p15;q21) translocation is a very rare recurrent cytogenetic aberration, and produced ZMYND11::MBTD1 fusion gene. To date, nine cases of acute leukemia with the t(10;17)(p15;q21) translocation have been reported, but the case of AML with ZMYND11::MBTD1 after chemotherapy and radiotherapy have not been reported. Epirubicin-based chemotherapy or radiotherapy for breast cancer increases the risk of developing secondary leukemia. We report a case of AML with the ZMYND11::MBTD1 fusion gene that developed after epirubicin-based chemotherapy and radiotherapy for breast cancer. previous chemotherapy and radiotherapy may be associated with poor prognosis of AML with ZMYND11/MBTD1.

t(10;17)(p15;q21)易位是一种非常罕见的复发性细胞遗传畸变,并产生ZMYND11::MBTD1融合基因。迄今为止,已有九例 t(10;17)(p15;q21)易位的急性白血病病例报道,但化疗和放疗后出现 ZMYND11::MBTD1 融合基因的急性髓细胞性白血病病例尚未见报道。以表柔比星为基础的乳腺癌化疗或放疗会增加罹患继发性白血病的风险。我们报告了一例乳腺癌患者在接受以表柔比星为基础的化疗和放疗后出现的ZMYND11::MBTD1融合基因型急性髓细胞白血病。
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引用次数: 0
THE PROGNOSTIC IMPACT OF ERYTHROID DYSPLASIA IN APLASTIC ANEMIA AND MYELODYSPLASTIC NEOPLASMS WITH SINGLE-LINEAGE DYSPLASIA 红细胞发育不良对再生障碍性贫血和骨髓增生异常性肿瘤单系发育不良的预后影响
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100415
T. Maeda , A. Matsuda , J. Kanda , H. Kawabata , T. Ishikawa , K. Tohyama , A. Kitanaka , K. Araseki , K. Shimbo , T. Hata , T. Suzuki , H. Kayano , K. Usuki , M. Shindo-Ueda , N. Arima , M. Nohgawa , A. Ohta , S. Chiba , Y. Miyazaki , S. Nakao , K. Mitani

Introduction

While genetic aberrations are becoming increasingly critical in disease classification, morphological abnormalities defined by a 10% threshold in each lineage continue to play a significant role as a diagnostic tool for myelodysplastic neoplasms (MDS). However, erythroid lineage dysplasia has been reported in some cases of aplastic anemia (AA), a phenomenon noted as common in the UK guidelines.

Methods

We assessed the impact of erythroid dysplasia on the survival in AA patients enrolled in an ongoing prospective registry, central morphological review (blinded), and follow-up study of AA and MDS conducted by the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Furthermore, we compared the prognosis of AA patients with erythroid dysplasia with that of patients diagnosed in the same study with MDS presenting with single-lineage erythroid dysplasia (“MDS-SLED”). According to this study's definition, the criteria for excluding MDS are stringent, considering both bone marrow cellularity and megakaryocyte counts. Therefore, AA is not diagnosed when a decrease is not observed in the megakaryocyte count.

Results

The study included a total of 32 cases of AA with erythroid dysplasia, 56 cases of AA without dysplasia, and 47 cases of MDS-SLED. The overall survival or leukemia-free survival showed no significant difference between AA patients with and without erythroid dysplasia (both p=0.14). Nevertheless, distinct differences were seen between AA with erythroid dysplasia and those diagnosed with MDS-SLED (both p<0.0001).

Conclusions

Erythroid dysplasia should not exclude an AA diagnosis. In particular, megakaryocyte count plays an important role in differentiating between MDS from AA.

导言虽然基因畸变在疾病分类中变得越来越重要,但作为骨髓增生异常性肿瘤(MDS)的诊断工具,各系10%阈值定义的形态学异常仍发挥着重要作用。我们评估了红系发育不良对参加日本全国特发性骨髓衰竭综合征研究小组正在进行的前瞻性登记、中央形态学审查(盲法)以及 AA 和 MDS 随访研究的 AA 患者生存率的影响。此外,我们还将患有红细胞发育不良的 AA 患者的预后与同一研究中确诊的患有单系红细胞发育不良的 MDS("MDS-SLED")患者的预后进行了比较。根据该研究的定义,排除 MDS 的标准非常严格,既要考虑骨髓细胞性,又要考虑巨核细胞计数。因此,如果未观察到巨核细胞计数减少,则不能诊断为 AA。结果该研究共纳入 32 例伴红细胞发育不良的 AA 患者、56 例无发育不良的 AA 患者和 47 例 MDS-SLED 患者。有红细胞发育不良和无红细胞发育不良的AA患者的总生存率和无白血病生存率无明显差异(P均=0.14)。结论红细胞发育不良不应排除 AA 的诊断。结论红细胞发育不良不应排除 AA 的诊断,尤其是巨核细胞计数在区分 MDS 和 AA 方面起着重要作用。
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引用次数: 0
MACHINE-LEARNING-BASED PREDICTIVE CLASSIFIER FOR BONE MARROW FAILURE SYNDROME USING COMPLETE BLOOD COUNT AND CELL POPULATION DATA 利用全血细胞计数和细胞群数据,基于机器学习的骨髓衰竭综合征预测分类器
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100419
J. Seo , C. Lee , Y. Koh , C.H. Sun , J.-M. Lee , H. An , M. Kim

Introduction

Accurate risk assessment of bone marrow failure syndrome (BMFS) is crucial for early diagnosis and intervention.

Methods

We used complete blood count (CBC) data to develop a predictive model for BMFS. Retrospective CBC data were collected from Seoul National University Hospital and Seoul St. Mary's Hospital of the Catholic Medical Center in South Korea. We developed binary classifiers for aplastic anaemia (AA) and myelodysplastic syndrome (MDS) and generated a BMFS classifier to determine the maximum probability. Classifiers were developed using multiple feature sets consisting of 13, 17, 25, or 28 CBC features to ensure applicability to various CBC testing settings. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results

XGBoost achieved the best AUROCs, 0·953–0·961 for the AA classifier and 0·910–0·935 for the MDS classifier, across multiple CBC feature sets. The BMFS classifier, combining the AA and MDS classifiers, demonstrated an AUROC of 0·915–0·936. When using cut-off probabilities to achieve a 95% sensitivity, the specificities ranged from 68% to 79%. External validation on an independent dataset yielded an AUROC of 0·932–0·942, a sensitivity of 93–96%, and a specificity of 65–82% at the aforementioned cut-offs.

Conclusions

Our predictive model provides a practical guide for diagnosing BMFS based on basic demographics and CBC data available during the first clinical encounter. It provides a reliable risk assessment tool for primary physicians, facilitating a more effective triage, timely referrals, and improved patient care.

简介:准确评估骨髓衰竭综合征(BMFS)的风险对于早期诊断和干预至关重要。我们利用全血细胞计数数据开发了骨髓衰竭综合征的预测模型。我们从韩国首尔国立大学医院和天主教医疗中心首尔圣玛丽医院收集了回顾性全血细胞计数数据。我们开发了再生障碍性贫血(AA)和骨髓增生异常综合征(MDS)的二元分类器,并生成了一个 BMFS 分类器,以确定最大概率。分类器的开发使用了由 13、17、25 或 28 个 CBC 特征组成的多个特征集,以确保适用于各种 CBC 测试环境。在多个 CBC 特征集中,XGBoost 取得了最佳的 AUROCs,AA 分类器为 0-953-0-961,MDS 分类器为 0-910-0-935。结合 AA 和 MDS 分类器的 BMFS 分类器的 AUROC 为 0-915-0-936。当使用临界概率达到 95% 的灵敏度时,特异性介于 68% 到 79% 之间。在一个独立数据集上进行外部验证后发现,在上述临界值下,AUROC 为 0-932-0-942,灵敏度为 93%-96%,特异度为 65%-82%。结论我们的预测模型为诊断 BMFS 提供了一个实用指南,该指南基于基本人口统计学和首次临床会诊时获得的全血细胞计数数据。它为基层医生提供了可靠的风险评估工具,有助于更有效地进行分诊、及时转诊和改善患者护理。
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引用次数: 0
MITOTIC PERTURBATION IS A KEY MECHANISM OF ACTION OF DECITABINE IN MYELOID TUMOR TREATMENT 有丝分裂扰动是地西他滨治疗骨髓肿瘤的关键作用机制
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100446
T. Yabushita , T. Chinen , D. Kitagawa , T. Kitamura , S. Goyama

Introduction

Decitabine (DAC) is an epigenetic drug clinically used for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, its exact mechanism of action is unclear.

Methods

To uncover the mechanisms underlying resistance to HMA, we performed genome-scale CRISPR activation screen using murine MDS/AML cells expressing ASXL1 and SETBP1 mutants (cSAM).

Results

Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. In addition, transcriptome and metabolome analyses combined with our screen revealed the involvement of cholesterol metabolism in DAC resistance. Inhibition of cholesterol synthesis using statins delayed mitotic progression, suggesting that cholesterol is also important for proper mitosis. Moreover, co-treatment with DAC and statin caused mitotic catastrophe and showed synergistic growth-inhibitory effects in leukemia cells.

Conclusions

These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

简介:地西他滨(DAC)是一种表观遗传药物,临床上用于治疗骨髓增生异常综合征(MDS)和急性髓性白血病(AML)。为了揭示HMA耐药性的机制,我们使用表达ASXL1和SETBP1突变体(cSAM)的小鼠MDS/AML细胞进行了基因组规模的CRISPR激活筛选。结果我们使用MDS衍生的AML细胞进行的全基因组CRISPR-dCas9激活筛选表明,有丝分裂调节对DAC耐药性至关重要。在临床浓度下,DAC 能强烈诱导人类骨髓肿瘤中的异常有丝分裂(脱落失败或三极有丝分裂),尤其是在那些有 TP53 突变或先兆血液病的肿瘤中。在去除了 DNMT1 的细胞中,这种由 DAC 引发的有丝分裂紊乱和细胞凋亡会明显减弱。与此相反,Dnmt1 的过表达,而非催化无活性突变体的过表达,会增强 DAC 诱导的骨髓肿瘤有丝分裂缺陷。我们还证明,药物抑制 ATR-CLSPN-CHK1 通路可增强 DAC 诱导的有丝分裂破坏。此外,转录组和代谢组分析与我们的筛选相结合,揭示了胆固醇代谢参与了 DAC 抗性。使用他汀类药物抑制胆固醇合成可延缓有丝分裂进程,这表明胆固醇对正常的有丝分裂也很重要。此外,DAC 和他汀类药物联合处理会导致有丝分裂灾难,并对白血病细胞的生长产生协同抑制作用。这些数据对目前认为 DAC 通过抑制 DNMT1 和随后的 DNA 低甲基化来抑制白血病发生的假设提出了质疑,并强调了 DAC 通过异常的 DNMT1-DNA 共价键破坏有丝分裂的强大活性。
{"title":"MITOTIC PERTURBATION IS A KEY MECHANISM OF ACTION OF DECITABINE IN MYELOID TUMOR TREATMENT","authors":"T. Yabushita ,&nbsp;T. Chinen ,&nbsp;D. Kitagawa ,&nbsp;T. Kitamura ,&nbsp;S. Goyama","doi":"10.1016/j.lrr.2024.100446","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100446","url":null,"abstract":"<div><h3>Introduction</h3><p>Decitabine (DAC) is an epigenetic drug clinically used for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, its exact mechanism of action is unclear.</p></div><div><h3>Methods</h3><p>To uncover the mechanisms underlying resistance to HMA, we performed genome-scale CRISPR activation screen using murine MDS/AML cells expressing ASXL1 and SETBP1 mutants (cSAM).</p></div><div><h3>Results</h3><p>Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. In addition, transcriptome and metabolome analyses combined with our screen revealed the involvement of cholesterol metabolism in DAC resistance. Inhibition of cholesterol synthesis using statins delayed mitotic progression, suggesting that cholesterol is also important for proper mitosis. Moreover, co-treatment with DAC and statin caused mitotic catastrophe and showed synergistic growth-inhibitory effects in leukemia cells.</p></div><div><h3>Conclusions</h3><p>These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000360/pdfft?md5=2b1491f56cdd45cbc1b15efc15f2ef43&pid=1-s2.0-S2213048924000360-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Successful treatment with blinatumomab for acute lymphoblastic leukemia in an older adult patient complicated with hepatocarcinoma 用 blinatumomab 成功治疗一名并发肝癌的老年急性淋巴细胞白血病患者
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100413
Masuho Saburi , Masanori Sakata , Rika Maruyama , Yousuke Kodama , Keiichi Uraisami , Hiroyuki Takata , Yasuhiko Miyazaki , Katsuya Kawano , Yasuhiro Kodama , Eiichi Ohtsuka

An 82-year-old man with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) complicated by hepatocarcinoma was presented. Remission induction therapy of hyper-CVAD with half dose reduction achieved hematological complete remission (CR), but accompanied with elevated alanine aminotransferase and hyperbilirubinemia. The patient was thought intolerable for hyper-CVAD with half dose reduction due to liver toxicity, and treatment was switched to blinatumomab. Hematological CR was sustained after nine cycles of blinatumomab without exacerbation of liver dysfunction. After five courses of blinatumomab, hepatocarcinoma was treated successfully by trans-arterial chemoembolization. Two years after the diagnosis of ALL, the patient was alive in CR status of ALL.

患者是一名 82 岁的男性,患有费城染色体阴性急性淋巴细胞白血病(ALL)并发肝癌。减半剂量的高CVAD缓解诱导治疗取得了血液学完全缓解(CR),但伴有丙氨酸氨基转移酶升高和高胆红素血症。由于肝脏毒性,该患者被认为不能耐受减半剂量的超CVAD治疗,因此改用blinatumomab治疗。经过9个周期的blinatumomab治疗后,血液学CR得以维持,肝功能异常没有加重。5个疗程的blinatumomab治疗后,经动脉化疗栓塞术成功治疗了肝癌。确诊为 ALL 两年后,患者仍以 ALL CR 状态存活。
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引用次数: 0
NEW SHOWINGS OF 5Q- SYNDROME BASED ON SERIAL MEASUREMENTS OF BAALC-EXPRESSING STEM CELLS BURDEN IN BONE MARROW. 根据对骨髓中表达 baalc 的干细胞负荷的连续测量,发现了 5q- 综合征的新迹象。
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100423
A. Shakirova, M. Latypova, T. Gindina, N. Mamaev

Introduction

The 5q- deletion is macrocytic anemia syndrome with special clinical characteristics and relatively longer median survival with low probability of AML progression. The classification of this disease as MDS is still under debates. Molecular studies, such as tracking the leukemia-associated marker BAALC, may clarify this issue. Here we evaluated BAALC-expressing stem cells (BAALC-e SCs) in patient's with isolated 5q- syndrome and with different chromosomal abnormalities.

Methods

The study includes analysis of bone marrow (BM) from 16 patients with isolated 5q deletion and 15 samples of 5q- combined with additional non-identical chromosomal abnormalities. BMs from 10 MDS patients without 5q- but carrying other cytogenetic aberrations were studied as control group. Serial measurements of BAALC-e SCs were performed by qPCR using BAALC RQ Kit (Inogene, Russia). Cytogenetic study included standard karyotyping and FISH.

Results

The data analysis revealed that only 10% (2/16) of patients with isolated 5q- had BAALC gene overexpression. Further on, low BAALC-expressing stem cells were characteristic also in the group of 5q- combined with additional non-identical chromosomal aberrations (56%). Meanwhile, in control group this rate was higher (100%).

Conclusions

The presented data of BAALC-e SCs burdens in patients with isolated 5q- syndrome indicate that this pathology differs from typical MDS and can be considered as ribosomopathy with low risk of transformation to MDS or AML. From this position, the biological advantages of 5q deletion syndrome are obvious as an optimal clinical model for further study of MDS and AML formation at the level of leukemia-initiating cells.

导言5q缺失是一种巨幼红细胞贫血综合征,具有特殊的临床特征,中位生存期相对较长,急性髓细胞性贫血进展的概率较低。将这种疾病归类为 MDS 仍有争议。分子研究(如追踪白血病相关标记物 BAALC)可能会澄清这一问题。在此,我们评估了孤立5q-综合征和不同染色体异常患者的BAALC表达干细胞(BAALC-e SCs)。作为对照组,研究了 10 例无 5q 缺失但携带其他细胞遗传学畸变的 MDS 患者的骨髓。使用 BAALC RQ Kit(俄罗斯 Inogene 公司)通过 qPCR 对 BAALC-e SCs 进行序列测定。结果数据分析显示,只有10%(2/16)的孤立5q-患者有BAALC基因过表达。此外,在5q-合并其他非相同染色体畸变组(56%)中,BAALC干细胞表达量也较低。结论所展示的孤立5q-综合征患者BAALC-e干细胞负担数据表明,这种病理变化不同于典型的MDS,可被视为核糖体病,转化为MDS或AML的风险较低。从这个角度看,5q缺失综合征的生物学优势显而易见,它是在白血病启动细胞水平上进一步研究 MDS 和 AML 形成的最佳临床模型。
{"title":"NEW SHOWINGS OF 5Q- SYNDROME BASED ON SERIAL MEASUREMENTS OF BAALC-EXPRESSING STEM CELLS BURDEN IN BONE MARROW.","authors":"A. Shakirova,&nbsp;M. Latypova,&nbsp;T. Gindina,&nbsp;N. Mamaev","doi":"10.1016/j.lrr.2024.100423","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100423","url":null,"abstract":"<div><h3>Introduction</h3><p>The 5q- deletion is macrocytic anemia syndrome with special clinical characteristics and relatively longer median survival with low probability of AML progression. The classification of this disease as MDS is still under debates. Molecular studies, such as tracking the leukemia-associated marker <em>BAALC</em>, may clarify this issue. Here we evaluated <em>BAALC</em>-expressing stem cells (<em>BAALC</em>-e SCs) in patient's with isolated 5q- syndrome and with different chromosomal abnormalities.</p></div><div><h3>Methods</h3><p>The study includes analysis of bone marrow (BM) from 16 patients with isolated 5q deletion and 15 samples of 5q- combined with additional non-identical chromosomal abnormalities. BMs from 10 MDS patients without 5q- but carrying other cytogenetic aberrations were studied as control group. Serial measurements of <em>BAALC</em>-e SCs were performed by qPCR using BAALC RQ Kit (Inogene, Russia). Cytogenetic study included standard karyotyping and FISH.</p></div><div><h3>Results</h3><p>The data analysis revealed that only 10% (2/16) of patients with isolated 5q- had <em>BAALC</em> gene overexpression. Further on, low <em>BAALC</em>-expressing stem cells were characteristic also in the group of 5q- combined with additional non-identical chromosomal aberrations (56%). Meanwhile, in control group this rate was higher (100%).</p></div><div><h3>Conclusions</h3><p>The presented data of <em>BAALC</em>-e SCs burdens in patients with isolated 5q- syndrome indicate that this pathology differs from typical MDS and can be considered as ribosomopathy with low risk of transformation to MDS or AML. From this position, the biological advantages of 5q deletion syndrome are obvious as an optimal clinical model for further study of MDS and AML formation at the level of leukemia-initiating cells.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221304892400013X/pdfft?md5=418d9db7b324d20272e66defd848c656&pid=1-s2.0-S221304892400013X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
FAMILIAL SAMD9L MUTATION WWTH VARIABLE CLINICAL PHENOTYPE OF MDS/AML MONOSOMY 7 AND APLASTIC ANEMIA: A CASE OF TWO AFFECTED SIBLINGS.. 家族性SAMD9L突变与MDS/AML单体7型和再生障碍性贫血的可变临床表型:两个受影响兄弟姐妹的病例.
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100417
K. Albiroty, A. Al Mughairy

Introduction

SAMD9L mutation has been associated with hematological malignancies. The mutation has diverse hematological phenotypes ranging from Myelodysplastic syndrome (MDS) to Acute myeloid leukemia (AML)involving chromosome 7 aberration and recently described the emerging phenotype of aplastic anemia. We report two siblings with SAMD9L germline mutation born to asymptomatic consanguineous parents. each with different hematological phenotype.

Methods

Case #1: A 7- year old girl presented with thrombocytopenia & 4% peripheral blasts. She has no dysmorphic features . Family history is negative for hematological malignancies or BMF. She was diagnosed with MDS- Monomsomy7 . She transformed to AML over few weeks During this period her sibling presented with aplastic anemia, his (WES) revealed germline SAMD9L mutation which was detected in his sister . During chemotherapy of AED; there was interrupted due to septic shock so She was bridged with (Azacitadine + Venetoclax) prior to haploidentical BMT Case#2: A10- week old male presented with respiratory symptoms. He was diagnosed with Aplastic anemia and CMV pneumonitis .He was not dysmorphic WES revealed germline SAMD9L Mutation. although normal immunology workup, Natural Killer cell dysfunction was suspected based on SAMD9L mutation detection, early age of presentation, & resistant CMV-Viremia. He was treated for CMV infection and decided for haploidentical BMT

Results

We suggest to include SAMD9/SAMD9L in the standard AMLMDS genetic panel if additional system involved like immunodeficiency, neurological or genitourinary anomaly.

Conclusions

the heterogeneity of SAMD9L mutation even in family. High index of suspicious of this germline mutation is warranted in children with MDS.

导言SAMD9L突变与血液恶性肿瘤有关。该基因突变具有多种血液学表型,从骨髓增生异常综合征(MDS)到急性髓性白血病(AML),涉及7号染色体畸变,最近还描述了再生障碍性贫血的新表型。我们报告了两对 SAMD9L 基因突变的同胞兄弟姐妹,他们的父母均为无症状的近亲结婚者,各自具有不同的血液学表型。她没有畸形特征。家族史中没有血液恶性肿瘤或BMF。她被诊断为 MDS-单核细胞增多症 7。在此期间,她的兄弟姐妹出现了再生障碍性贫血,他(WES)的种系SAMD9L基因突变在他姐姐身上也被检测到。在 AED 化疗期间,她因脓毒性休克而中断化疗,因此在进行单倍体骨髓移植之前,她接受了(阿扎胞胺 + Venetoclax)治疗。虽然免疫学检查结果正常,但根据 SAMD9L 突变检测结果、发病年龄、抗药性 CMV 病毒血症等情况,怀疑自然杀伤细胞功能障碍。我们建议,如果涉及免疫缺陷、神经系统或泌尿生殖系统异常等其他系统,应将 SAMD9/SAMD9L 纳入标准 AMLMDS 基因检测。结论:SAMD9L 基因突变具有异质性,即使在家族中也是如此。
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引用次数: 0
KRAS MOSAIC MUTATION AND ITS TISSUE SPECIFICITY IN JUVENILE MYELOMONOCYTIC LEUKEMIA 幼年骨髓单核细胞白血病中的 kras 马赛克突变及其组织特异性
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100436
N. Takasugi , A. Sato , K. Koh , A. Nakazawa , M. Kato

Introduction

Somatic or germline mutations in genes regulating Ras-MAPK pathway have been identified in majority of Juvenile myelomonocytic leukemia (JMML) cases. Mosaicism of KRAS and NRAS mutations in JMML were reported, with variation in the proportion of cells carrying these mutations across different organs. However, how this proportion is distributed across different organs had not been clarified whereas prevalence of somatic oncogenic KRAS mutations are known.

Methods

Our study focused on one JMML patient with mosaic KRAS G12D mutation and uniparental disomy at the 12p locus, who developed aggressive transformation, invasion into multiple organs and subsequently died. DNA from FFPE biopsy samples of eighteen organs were analyzed using mutation-specific digital PCR (dPCR). The variant allele frequency (VAF) of KRAS G12D and hetero SNP at the 12p locus were analyzed in each samples to remove the impact of mutation by infiltrating tumor cells and to estimate the percentage of KRAS mutant cells.

Results

KRAS G12D mutations were identified in samples from sixteen of eighteen analyzed tissues. The frequency of KRAS G12D mutated alleles varied among different tissue type and the median VAF was 5.9% (2.0% -29.3%). The VAF were relatively high in gastrointestinal tract (stomach, colon, ileum), liver and spleen, whereas the VAF were low or undetected in testis, heart and spinal cord.

Conclusions

Our findings suggest that KRAS mosaic mutations can exhibit tissue specificity like somatic oncogenic mutations. These tissue distribution might be associated with pathogenesis of JMML and other types of cancer with mosaicism.

导言:在大多数幼髓单核细胞白血病(JMML)病例中发现了Ras-MAPK通路调控基因的基因突变或种系突变。有报告称,JMML 中的 KRAS 和 NRAS 突变具有嵌合性,不同器官中携带这些突变的细胞比例存在差异。我们的研究重点是一名患有马赛克KRAS G12D突变和12p位点单亲裂殖症的JMML患者,他发生了侵袭性转化,侵犯了多个器官,随后死亡。研究人员使用突变特异性数字 PCR(dPCR)分析了 18 个器官的 FFPE 活检样本中的 DNA。分析了每个样本中 KRAS G12D 的变异等位基因频率(VAF)和 12p 位点的杂合 SNP,以排除肿瘤细胞浸润突变的影响,并估计 KRAS 突变细胞的百分比。KRAS G12D 突变等位基因的频率因组织类型而异,中位 VAF 为 5.9% (2.0% -29.3%)。胃肠道(胃、结肠、回肠)、肝脏和脾脏的 VAF 相对较高,而睾丸、心脏和脊髓的 VAF 较低或未检出。我们的研究结果表明,KRAS镶嵌突变可以像体细胞致癌突变一样表现出组织特异性,这些组织分布可能与 JMML 及其他类型镶嵌型癌症的发病机制有关。
{"title":"KRAS MOSAIC MUTATION AND ITS TISSUE SPECIFICITY IN JUVENILE MYELOMONOCYTIC LEUKEMIA","authors":"N. Takasugi ,&nbsp;A. Sato ,&nbsp;K. Koh ,&nbsp;A. Nakazawa ,&nbsp;M. Kato","doi":"10.1016/j.lrr.2024.100436","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100436","url":null,"abstract":"<div><h3>Introduction</h3><p>Somatic or germline mutations in genes regulating Ras-MAPK pathway have been identified in majority of Juvenile myelomonocytic leukemia (JMML) cases. Mosaicism of <em>KRAS</em> and <em>NRAS</em> mutations in JMML were reported, with variation in the proportion of cells carrying these mutations across different organs. However, how this proportion is distributed across different organs had not been clarified whereas prevalence of somatic oncogenic <em>KRAS</em> mutations are known.</p></div><div><h3>Methods</h3><p>Our study focused on one JMML patient with mosaic <em>KRAS</em> G12D mutation and uniparental disomy at the 12p locus, who developed aggressive transformation, invasion into multiple organs and subsequently died. DNA from FFPE biopsy samples of eighteen organs were analyzed using mutation-specific digital PCR (dPCR). The variant allele frequency (VAF) of <em>KRAS</em> G12D and hetero SNP at the 12p locus were analyzed in each samples to remove the impact of mutation by infiltrating tumor cells and to estimate the percentage of <em>KRAS</em> mutant cells.</p></div><div><h3>Results</h3><p><em>KRAS</em> G12D mutations were identified in samples from sixteen of eighteen analyzed tissues. The frequency of <em>KRAS</em> G12D mutated alleles varied among different tissue type and the median VAF was 5.9% (2.0% -29.3%). The VAF were relatively high in gastrointestinal tract (stomach, colon, ileum), liver and spleen, whereas the VAF were low or undetected in testis, heart and spinal cord.</p></div><div><h3>Conclusions</h3><p>Our findings suggest that <em>KRAS</em> mosaic mutations can exhibit tissue specificity like somatic oncogenic mutations. These tissue distribution might be associated with pathogenesis of JMML and other types of cancer with mosaicism.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000268/pdfft?md5=75171d6574de57b01fac22c459f88044&pid=1-s2.0-S2213048924000268-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Leukemia Research Reports
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