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Venetoclax for an ATRA and ATO resistance acute promyelocytic leukemia patient with TNRC18::RARA fusion gene Venetoclax 治疗 TNRC18::RARA 融合基因的 ATRA 和 ATO 抗性急性早幼粒细胞白血病患者
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100482
Variant acute promyelocytic leukemia (APL) poses diagnostic and therapeutic challenges primarily because of the absence of PML::RARA. This report presents the case of a patient diagnosed with all-trans retinoic acid (ATRA)-resistant APL harboring the TNRC18::RARA fusion gene. After treatment with venetoclax, azacitidine, and ATRA, the patient achieved complete remission. The patient also developed pulmonary tuberculosis and a multidrug-resistant infection, which improved considerably after antituberculosis treatment and carrimycin, respectively.
变异型急性早幼粒细胞白血病(APL)给诊断和治疗带来了挑战,主要原因是缺乏 PML::RARA。本报告介绍了一例被诊断为携带 TNRC18::RARA 融合基因的全反式维甲酸(ATRA)耐药 APL 患者的病例。在接受venetoclax、阿扎胞苷和ATRA治疗后,患者获得了完全缓解。该患者还患上了肺结核和耐多药感染,在分别接受抗结核治疗和卡林霉素治疗后,病情有了很大改善。
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引用次数: 0
THE ROLE OF LET-7/HMGA2 LINKAGE IN THE PATHOGENESIS AND PROGNOSIS OF MYELODYSPLASTIC NEOPLASMS LET-7/HMGA2连锁在骨髓增生异常性肿瘤的发病机制和预后中的作用
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100428
D. Vlachopoulou , C.-N. Kontandreopoulou , P.T. Diamantopoulos , S. Syriopoulou , C. Stafylidis , P. Katsiampoura , A. Galanopoulos , M. Dimou , P. Panayiotidis , N.-A. Viniou

Introduction

MicroRNAs (miRNAs),are significant regulators of human hematopoietic stem cells. Their deregulation contributes to hematological malignancies.The let-7 family has been found frequently deregulated in malignancies.In MDS various alterations of miRNAs have been reported.High Mobility Group AT-Hook 2 (HMGA2) protein functions as a transcriptional regulator. In this study, we investigated the HMGA2 expression in MDS and specifically in patients with fibrosis we studied the prognostic significance of four members of the let-7 family (let-7a, let-7b, let-7c, let-7d).

Methods

RNA extraction, reverse transcription, anda SYBR Green based real-time PCR were performed for the absolute quantification of HMGA2, using standard protocols. After RNA polyadenylation and reverse transcription with an oligo-dT adapter primer, miRNAs transcript levels were determined using the SYBR Green chemistry. IBM SPSS statistics, version 26 (IBM Corporation, North Castle, NY, USA) was used for the analysis.

Results

HMGA2 gene expression was investigated in 78 patients with MDS, whereas transcript levels of four members of the let-7 family (let-7a, let-7b, let-7c, let-7d) were analyzed in 11 patients with fibrosis. Let-7a transcript levels were significantly higher in MDS patients who developed acute myeloid leukemia (AML) compared to the group that did not (p=0.0141). Let-7d presented a negative correlation (p=0.0408). A moderate (p =0.0483) negative correlation of HMGA2 with let-7c, and a strong positive correlation (p =0.0481) with let-7d, were observed.

Conclusions

In literature, the let-7/HMGA2 linkage could be a signature in MDS pathogenesis. Let-7a level was found higher in transformation to AML,defining it as a poor prognostic factor, in contrast with the protective role of high let-7d.

导言微小RNA(miRNA)是人类造血干细胞的重要调节因子。在 MDS 中,miRNAs 的各种改变均有报道。高迁移率组 AT-Hook 2(HMGA2)蛋白具有转录调节因子的功能。在这项研究中,我们调查了 HMGA2 在 MDS 中的表达情况,特别是在纤维化患者中的表达情况,并研究了 let-7 家族四个成员(let-7a、let-7b、let-7c、let-7d)的预后意义。方法采用标准方案进行 RNA 提取、反转录和基于 SYBR Green 的实时 PCR,以绝对定量 HMGA2。用寡聚-dT 适配器引物进行 RNA 多腺苷酸化和反转录后,使用 SYBR Green 化学方法测定 miRNAs 的转录水平。结果 在 78 例 MDS 患者中调查了 HMGA2 基因的表达,在 11 例纤维化患者中分析了 let-7 家族四个成员(let-7a、let-7b、let-7c 和 let-7d)的转录水平。与未发展为急性髓性白血病(AML)的组别相比,发展为急性髓性白血病(AML)的 MDS 患者的 Let-7a 转录水平明显更高(P=0.0141)。Let-7d 呈负相关(p=0.0408)。HMGA2 与 let-7c 呈中度负相关(p=0.0483),与 let-7d 呈强正相关(p=0.0481)。Let-7a水平在向急性髓细胞性白血病转化时较高,是一个不良预后因素,与高let-7d的保护作用形成鲜明对比。
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引用次数: 0
PREDICTION OF POST-TRANSPLANT RELAPSE IN THE MYELODYSPLASTIC SYNDROMES VIA EVALUATION OF STEM CELLS 通过干细胞评估预测骨髓增生异常综合征移植后复发
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100434
S. Chung , B. Kroger , Y. Huang , A. Son , P. Carlsgaard , L. Pop , R. Vittrup , F. Kalkan , A. Cherukuri , D. Sallman , R. Tamari , C. Gurnari , J. Maciejewski , Y. Madanat

Introduction

Allogeneic stem cell transplant (alloSCT) remains the only curative treatment for the myelodysplastic syndromes (MDS), but relapse is common. Studies using error-corrected sequencing (ECS) on bulk bone marrow (BM) have shown that molecular residual disease is predictive of relapse. But the sensitivity of this approach is limited, and it is not known what cells give rise to relapse.

Methods

To test our hypothesis that hematopoietic stem cells (HSCs) drive post-transplant relapse, we developed a protocol to perform ECS on as few as <25 HSCs. We used this new tool to ask if post-transplant relapse originates from MDS HSCs, and whether their persistence predicts for relapse. We also sought to determine if curing MDS requires eradication of MDS HSCs, or whether they are simply suppressed by graft-versus-tumor effect.

Results

We sequenced HSCs, multipotent progenitors (MPPs), restricted progenitors, and bulk BM from 33 MDS patients who underwent alloSCT (with an additional 20 specimens to be presented). Persistence of mutations in HSCs/MPPs in the first 120 days post-transplant was 100% specific and 84% sensitive for relapse, while detection of mutations in bulk BM was only 41% sensitive and 85% specific (Figure). Average time from mutation detection in HSCs/MPPs to relapse was 6.9 months.

Conclusions

In conclusion, we have shown for the first time that relapse of MDS after allogeneic transplant is driven by failure to eradicate MDS HSCs, and that detection of MDS HSCs early after transplant is highly predictive for relapse. This can identify patients who may benefit from early post-transplant interventions to forestall relapse.

导言同种异体干细胞移植(alloSCT)仍是骨髓增生异常综合征(MDS)唯一可治愈的治疗方法,但复发很常见。对大量骨髓(BM)进行误差校正测序(ECS)的研究表明,分子残留疾病可预测复发。为了验证造血干细胞(HSCs)会导致移植后复发的假设,我们制定了一套方案,对少至25个造血干细胞进行ECS检测。我们利用这一新工具询问移植后复发是否源于MDS造血干细胞,以及造血干细胞的持续存在是否预示着复发。我们还试图确定治愈MDS是否需要根除MDS造血干细胞,或者它们是否只是受到移植物抗肿瘤效应的抑制。结果我们对33例接受异体移植的MDS患者(另外20例标本将提交)的造血干细胞、多能祖细胞(MPPs)、受限祖细胞和全血细胞进行了测序。移植后120天内造血干细胞/MPPs中突变的持续存在对复发的特异性为100%,敏感性为84%,而在全血细胞中检测到突变的敏感性仅为41%,特异性为85%(图)。从造血干细胞/骨髓造血干细胞中检测到突变到复发的平均时间为 6.9 个月。结论总之,我们首次证明了异基因移植后 MDS 复发的原因是未能根除 MDS 造血干细胞,而移植后早期 MDS 造血干细胞的检测对复发具有高度预测性。这可以确定哪些患者可能受益于移植后早期干预以防止复发。
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引用次数: 0
A novel mutation of LYST and haemophagocytic lymphohistiocytosis as the first symptom in children with ph+ALL: A case report and literature review 噬血细胞淋巴组织细胞增多症(ph+ALL)患儿的一种新型 LYST 基因突变和作为首发症状的噬血细胞淋巴组织细胞增多症:病例报告和文献综述
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100481
Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder. This study sheds light on a rare and intriguing case of HLH as the initial symptom in a child with Philadelphia chromosome-positive acute lymphoblastic leukaemia (ph+ALL). This case report, accompanied by a comprehensive literature review, highlights the diagnostic challenges and treatment complexities encountered in the management of such rare manifestations. Moreover, the identification of a novel mutation in the LYST gene adds a unique genetic perspective to the understanding of HLH pathogenesis, potentially opening avenues for further research in this area.
嗜血淋巴细胞增多症(HLH)是一种罕见疾病。本研究揭示了一例罕见而有趣的病例:HLH是一名费城染色体阳性急性淋巴细胞白血病(ph+ALL)患儿的初始症状。本病例报告附有全面的文献综述,强调了在处理此类罕见表现时所遇到的诊断挑战和治疗复杂性。此外,LYST基因新型突变的鉴定为人们了解HLH的发病机制增添了一个独特的遗传学视角,为该领域的进一步研究开辟了潜在的途径。
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引用次数: 0
IGLL5 controlled by super-enhancer affects cell survival and MYC expression in mature B-cell lymphoma 由超级增强子控制的 IGLL5 影响成熟 B 细胞淋巴瘤中细胞的存活和 MYC 的表达
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100451
Hiroki Hosoi , Shotaro Tabata , Hideki Kosako , Yoshikazu Hori , Tadashi Okamura , Yusuke Yamashita , Kota Fujimoto , Daiki Kajioka , Kentaro Suzuki , Motomi Osato , Gen Yamada , Takashi Sonoki

IGLL5 is shown to be located near super-enhancer (SE) in B-cell tumors, and this gene is frequently mutated and a target of translocation in B-cell tumors. These results suggest roles of the IGLL5 in tumorigenesis; however, its functional properties have been unclear. We found that two mature B-cell lymphoma cell lines expressed IGLL5 mRNA with Cλ1 segment. JQ1 treatment resulted in down-expression of IGLL5, indicating that IGLL5 is controlled by SE. IGLL5 knockdown induced cell death with down-expression of MYC. Our results suggested that IGLL5 might have a role in survival of mature B-cell tumors and involvement in MYC expression. (100 words)

在 B 细胞肿瘤中,IGLL5 位于超级增强子(SE)附近,而且该基因经常发生突变,是 B 细胞肿瘤的易位靶点。这些结果表明了 IGLL5 在肿瘤发生中的作用,但其功能特性尚不清楚。我们发现两种成熟的 B 细胞淋巴瘤细胞系表达带有 Cλ1 片段的 IGLL5 mRNA。JQ1处理导致IGLL5表达量下降,表明IGLL5受SE控制。敲除 IGLL5 会导致细胞死亡,同时降低 MYC 的表达。我们的研究结果表明,IGLL5 可能在成熟 B 细胞肿瘤的存活中发挥作用,并参与 MYC 的表达。(100字)
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引用次数: 0
Very late relapse of Burkitt's lymphoma in an EBV-negative patient after 20 years of complete remission 一名 EBV 阴性患者的伯基特淋巴瘤在完全缓解 20 年后极晚期复发
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100470

Burkitt's lymphoma (BL) is an aggressive B-cell lymphoma that occurs in children and adults. It is a chemosensitive lymphoma with very exceptional cases of late relapse.

We report the case of a 32-year-old male, originally from a nonendemic area for BL, who was successfully treated for abdominal BL 20 years ago. He described a two-month history of cervical swelling and a one-week history of dyspnea. Physical examination was unremarkable except for a left submandibular mass that extended to the collarbone. An ultrasound of the neck revealed cervical lymphadenopathy. The patient was submitted to a lymph node biopsy with an immunohistochemical analysis, which concluded to the diagnosis of BL. Screening for recent Epstein-Barr-Virus (EBV) infection was negative. We considered this a very late relapse (VLR) of the original disease, and the patient was treated according to the same initial protocol. Unfortunately, he suffered a second relapse and died.

We report an unusual case of a VLR of nonendemic BL in an EBV-negative patient, occurring 20 years after achieving complete remission following the initial chemotherapy.

伯基特淋巴瘤(BL)是一种侵袭性 B 细胞淋巴瘤,好发于儿童和成人。我们报告了一例 32 岁男性患者的病例,他来自布基特淋巴瘤非流行区,20 年前曾成功治疗过腹部布基特淋巴瘤。他自述有两个月的颈部肿胀史和一周的呼吸困难史。体格检查除左侧颌下肿块延伸至锁骨外无其他异常。颈部超声波检查发现颈部淋巴结病变。患者接受了淋巴结活检和免疫组化分析,最后确诊为 BL。最近的爱泼斯坦-巴氏病毒(EBV)感染筛查结果为阴性。我们认为这是原发疾病的极晚期复发(VLR),并按照相同的初始方案对患者进行了治疗。我们报告了一例不寻常的病例:EBV 阴性患者在首次化疗后获得完全缓解 20 年后,又出现了非流行性 BL 的 VLR。
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引用次数: 0
Avatrombopag for severe refractory thrombocytopenia in a pediatric patient with ALL following allogeneic hematopoietic stem cell transplantation: A case report 阿伐曲波帕治疗一名异基因造血干细胞移植后患有 ALL 的儿童患者的严重难治性血小板减少症:病例报告
IF 0.7 Q4 HEMATOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100472

Patients who receive allogeneic hematopoietic stem cell transplantation (alloHSCT) are at risk for developing persistent thrombocytopenia. Here, we describe treatment with avatrombopag, a thrombopoietin receptor agonist, in a pediatric patient with chronic, severe, transfusion-dependent thrombocytopenia (<10 × 103/µL) post-alloHSCT that was persistent despite treatment with romiplostim, another thrombopoietin receptor agonist. Following the granting of a compassionate use investigational new drug authorization, avatrombopag treatment was initiated, and the patient's platelet count increased. To date, the patient has maintained a platelet count >100 × 103/µL. No adverse events or medication toxicities have been reported, and he has resumed his pre-alloHSCT activities.

接受异基因造血干细胞移植(alloHSCT)的患者有可能患上持续性血小板减少症。在这里,我们描述了阿伐曲波帕(一种血小板生成素受体激动剂)对一名异体造血干细胞移植后慢性、严重、输血依赖性血小板减少症(10 × 103/µL)儿科患者的治疗。在获得研究性新药同情使用授权后,阿伐曲波帕开始治疗,患者的血小板计数也随之增加。迄今为止,患者的血小板计数一直保持在 100 × 103/µL。未报告任何不良事件或药物毒性,他已恢复了骨髓造血干细胞移植前的活动。
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引用次数: 0
PROVIDING TIMELY PATIENT-CENTERED MOLECULAR DIAGNOSTIC TESTING FOR PATIENTS WITH ACUTE MYELOID LEUKEMIA: A QUALITY IMPROVEMENT STUDY 为急性髓性白血病患者及时提供以患者为中心的分子诊断检测:质量改进研究
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100422
A. Qureshi , J. Ho , L. Schenkel , B. Chin-Yee , U. Deotare , A. Meybodi , L. Saini , B. Sadikovic , I. Chin-Yee

Introduction

At many centers, molecular diagnostic (MD) testing for Acute Myeloid Leukemia (AML) struggles to meet turn-around-time (TAT) required for therapeutic decision-making. At our tertiary referral centre, TAT for MD (karyotyping and next-generation sequencing [NGS]) exceeded 4 weeks, resulting in a 'quality gap' in our care pathway for AML. The goal of our study was to improve TAT for MD to optimize care for patients with AML/MDS.

Methods

A multidisciplinary team (hematologists, laboratory scientists, and hematopathologists) defined target TATs for each MD test based on guidelines and available therapies. TAT was evaluated from time of bone marrow to MD reporting. Retrospective review from 2021-2022 was performed to establish baseline time points to compare to post-intervention TATs. Root cause analysis was performed through stakeholder interviews to identify areas contributing to delays in TAT. The primary outcome was the ability to meet target TAT for MD.

Results

Baseline TAT for cytogenetics and NGS varied widely and exceeded targets (Figure 1). Root cause analysis identified lack standardized ordering and testing for patients with AML due to inconsistent decision-maker awareness. Laboratory factors included batching and lack prioritization of AML samples. Interventions included a standardized AML testing algorithm triggered reflexively by flow cytometry at the time diagnosis. Impact of laboratory triggered algorithm for AML testing is shown in Figure 1.

Conclusions

Shared decision-making between hematologists and laboratory practitioners to develop an algorithm for reflex testing and treatment of AML improved TAT. Further improvements are underway to acheive targets, and lessons will be used to inform care pathways for AML/MDS.

导言在许多中心,急性髓性白血病(AML)的分子诊断(MD)检测很难满足治疗决策所需的周转时间(TAT)。在我们的三级转诊中心,MD(核型和下一代测序 [NGS])的周转时间超过 4 周,导致我们的急性髓细胞白血病治疗路径存在 "质量差距"。我们的研究目标是改善 MD 的 TAT,以优化 AML/MDS 患者的治疗。方法一个多学科团队(血液学家、实验室科学家和血液病理学家)根据指南和现有疗法确定了每项 MD 检测的目标 TAT。评估从骨髓采集到 MD 报告的 TAT。对 2021-2022 年进行了回顾性审查,以确定基线时间点,并与干预后的 TAT 进行比较。通过利益相关者访谈进行了根本原因分析,以确定造成 TAT 延误的原因。主要结果是达到 MD 目标 TAT 的能力。结果细胞遗传学和 NGS 的基线 TAT 差异很大,超过了目标(图 1)。根本原因分析发现,由于决策者认识不一致,导致急性髓细胞性白血病患者缺乏标准化的排序和检测。实验室因素包括对急性髓细胞样本进行分批处理和缺乏优先排序。干预措施包括在诊断时通过流式细胞术触发标准化的急性髓细胞白血病检测算法。图 1 显示了实验室触发的急性髓细胞白血病检测算法的影响。结论血液学专家和实验室从业人员共同决策,制定急性髓细胞白血病条件反射检测和治疗算法,提高了 TAT。目前正在进一步改进,以实现目标,并将总结经验,为急性髓细胞性白血病/骨髓增生异常综合症的治疗路径提供参考。
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引用次数: 0
MITOCHONDRIAL FRAGMENTATION IS A NEW THERAPEUTIC TARGET AND DIAGNOSTIC CRITERIA FOR MYELODYSPLASTIC SYNDROMES. 线粒体碎片是骨髓增生异常综合征的新治疗靶点和诊断标准。
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100424
Y. Kamimura-Aoyagi , Y. Harada , K. Nomura , N. Matsunuma , K. Yuki , H. Kobayashi , Y. Hayashi , A. Hijikata , H. Harada

Introduction

Myelodysplastic syndromes (MDS) are characterized by persistent of cytopenia, gene abnormalities, and dysplasia. Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear.

Methods

Recently, we established a new MDS with low blasts (MDS-LB) model (CBLΔE8/9-RUNX1S291fs mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) .

Results

MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P<0.001, cutoff value 30.8%). The calculated cutoff value clearly distinguishes patients with MDS-LB and non-MDS cytopenia.

Conclusions

These data suggest that mitochondrial fragmentation can be not only a new therapeutic target of MDS-LB but also one category of dysplasia that can diagnose MDS-LB.

导言 骨髓增生异常综合征(MDS)的特征是持续的全血细胞减少、基因异常和发育不良。虽然慢性炎症和无效造血之间的相关性已被证实是 MDS 的发病机制,但其具体机制仍不清楚。方法最近,我们通过在小鼠造血干细胞和祖细胞(HSC/Ps)中引入这两个突变,建立了一种新的 MDS 低胚泡(MDS-LB)模型(CBLΔE8/9-RUNX1S291fs 小鼠),该模型再现了 MDS-LB 的发病机制,如泛血细胞减少和慢性炎症。重要的是,抑制线粒体碎片的药理作用通过抑制炎症信号激活来挽救 MDS 小鼠的白细胞减少症和发育不良的形成,这表明线粒体碎片可能是 MDS 的一个新的治疗靶点。鉴于线粒体碎片与 MDS 发病机制有关,我们假设线粒体碎片可用于 MDS 的形态学诊断。非 MDS 全血细胞减少症和 MDS-LB 患者的鉴别诊断一直具有挑战性。我们评估了 10 名健康人和 141 名接受疾病改变疗法前患者骨髓样本中的线粒体形态。与无发育不良和基因异常的全血细胞减少症患者相比,MDS-LB 患者线粒体破碎的细胞比例明显增加(平均 50.7% 对 22.4%,P<0.001,临界值 30.8%)。这些数据表明,线粒体碎片不仅是 MDS-LB 的一个新的治疗靶点,也是可以诊断 MDS-LB 的一类发育不良。
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引用次数: 0
KINOME EXPRESSION PROFILING FOR RISK STRATIFICATION OF MYELODYSPLASTIC SYNDROMES 用于骨髓增生异常综合征风险分层的激酶组表达谱分析
Q4 Medicine Pub Date : 2024-01-01 DOI: 10.1016/j.lrr.2024.100433
C.-Y. Yao , C.-C. Lin , Y.-H. Wang , C.-J. Kao , C.-H. Tsai , H.-A. Hou , H.-F. Tien , C.-L. Hsu , W.-C. Chou

Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous constellation of myeloid neoplasms originating from the clonal proliferation of aberrant hematopoietic stem cells (HSC). The human kinome, which comprises over five hundred kinases, plays a critical role in regulating numerous cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in MDS have not been investigated before.

Methods

Overall, 341 patients diagnosed with primary MDS according to the 2016 WHO classification, who had adequate cryopreserved diagnostic unsorted bone marrow (BM) samples for DNA and RNA sequencing, were recruited. The normalized gene expressions of a total of 517 kinase gene were studied. We first identified those kinases whose expressions were higher in MDS patients than in healthy controls, and then used LASSO-regularized Cox proportional hazards regression to identify prognostically significant kinases to construct the KInase Stratification Score (KISS).

Results

We discovered that the expression levels of seven kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, PRKCZ) could predict patient outcome, and we used these kinases to construct the KISS; we further validated its prognostic significance in two external MDS cohorts. A higher KISS was associated with older age, higher BM blast percentage, higher IPSS-R risk, complex karyotype, and mutations in several adverse-risk genes in MDS. In the multivariate analysis, a higher KISS was proved to be an independent unfavorable risk factor.

Conclusions

Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS, and inform novel therapeutic opportunities.

导言 骨髓增生异常综合征(MDS)是由异常造血干细胞(HSC)克隆性增殖引起的一种异质性髓系肿瘤。人类激酶组由五百多个激酶组成,在调节众多细胞功能方面发挥着至关重要的作用。方法共招募了341名根据2016年WHO分类诊断为原发性MDS的患者,这些患者有足够的冷冻保存的诊断性未分选骨髓(BM)样本用于DNA和RNA测序。共研究了517个激酶基因的归一化基因表达。我们首先确定了那些在MDS患者中表达量高于健康对照组的激酶,然后使用LASSO规则化的Cox比例危险回归确定了对预后有重要意义的激酶,并构建了激酶分层评分(KISS)。结果我们发现,7种激酶(PTK7、KIT、MAST4、NTRK1、PAK6、CAMK1D、PRKCZ)的表达水平可以预测患者的预后,我们利用这些激酶构建了KISS;我们在两个外部MDS队列中进一步验证了其预后意义。KISS值越高,与年龄越大、血细胞鼓泡百分比越高、IPSS-R风险越高、核型复杂以及MDS中多个不良风险基因突变有关。结论总之,我们的研究结果表明,KISS有可能改善目前的MDS预后方案,并提供新的治疗机会。
{"title":"KINOME EXPRESSION PROFILING FOR RISK STRATIFICATION OF MYELODYSPLASTIC SYNDROMES","authors":"C.-Y. Yao ,&nbsp;C.-C. Lin ,&nbsp;Y.-H. Wang ,&nbsp;C.-J. Kao ,&nbsp;C.-H. Tsai ,&nbsp;H.-A. Hou ,&nbsp;H.-F. Tien ,&nbsp;C.-L. Hsu ,&nbsp;W.-C. Chou","doi":"10.1016/j.lrr.2024.100433","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100433","url":null,"abstract":"<div><h3>Introduction</h3><p>Myelodysplastic syndrome (MDS) is a heterogeneous constellation of myeloid neoplasms originating from the clonal proliferation of aberrant hematopoietic stem cells (HSC). The human kinome, which comprises over five hundred kinases, plays a critical role in regulating numerous cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in MDS have not been investigated before.</p></div><div><h3>Methods</h3><p>Overall, 341 patients diagnosed with primary MDS according to the 2016 WHO classification, who had adequate cryopreserved diagnostic unsorted bone marrow (BM) samples for DNA and RNA sequencing, were recruited. The normalized gene expressions of a total of 517 kinase gene were studied. We first identified those kinases whose expressions were higher in MDS patients than in healthy controls, and then used LASSO-regularized Cox proportional hazards regression to identify prognostically significant kinases to construct the KInase Stratification Score (KISS).</p></div><div><h3>Results</h3><p>We discovered that the expression levels of seven kinases (<em>PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, PRKCZ</em>) could predict patient outcome, and we used these kinases to construct the KISS; we further validated its prognostic significance in two external MDS cohorts. A higher KISS was associated with older age, higher BM blast percentage, higher IPSS-R risk, complex karyotype, and mutations in several adverse-risk genes in MDS. In the multivariate analysis, a higher KISS was proved to be an independent unfavorable risk factor.</p></div><div><h3>Conclusions</h3><p>Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS, and inform novel therapeutic opportunities.</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/S2213048924000232/pdfft?md5=c610a93c5930abf41034806f87be75a7&pid=1-s2.0-S2213048924000232-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103599","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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