Damage Mechanism of CK2 and IKAROS in Philadelphia Like Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).

Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy

Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has been demonstrated in acute lymphoblastic leukemia(ALL),of which ALL with Philadelphia chromosome-positive(Ph+).The use of imatinib,a tyrosine kinase inhibitor(TKI),as part of front-line treatment and in combination with cytotoxic agents,has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL.New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations.An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs,such as nilotinib and dasatinib.However,in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells.None of the TKIs in clinical use target the LSC.Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs.Allogeneic stem cell transplantation(SCT) remains the only curative treatment available for these patients.Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations.Hence,TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy.Better understanding the biology of Ph+ ALL will open new avenues for effective management.In this review,we highlight recent findings relating to the question of LSCs in Ph+ ALL.

The Philadelphia chromosome in leukemogenesis

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs:A literature review

Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.

Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib

Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.

Unusual cytogenetic abnormalities associated with Philadelphia chromosome

Cytogenetic abnormalities are the hallmark of leukemias. We report here two cases of unusual cytogenetic abnormalities associated with Philadelphia chromosome, one with mixed phenotypic acute leukemia showing monosomy 7 and t(9;22)(q34;q11.2) and the other with chronic myeloid leukemia and additional translocation involving chromosomes 10 and 13. Both patients achieved complete remission following imatinib based treatment.

China Tourism Goes to Philadelphia Travel & Adventure Show

The Sixth Philadelphia Travel & Adventure Show took place at Pennsylvania Convention Center in Philadelphia, the USA, from March 9 to 1 0. China National Tourist Office, New York, used pandas and Peking Opera symbolic meaning as the key visual style,"Beautiful China" national tourism brand as the theme to present "China Beyond Imaginations , in Philadelphia, delivered news about tourism in China and caught attention of lots of participants.

NCPA May Festival 2019 Closing Concert: The Philadelphia Orchestra

Date: May 17-18, 2019 Venue: National Center for the Performing Arts Prices: RMB 280, 480, 600, 780, 900, 1080, 1280 The Philadelphia Orchestra is one of the preeminent orchestras in the world, renowned for its distinctive sound, desired for its keen ability to capture the hearts and imaginations of audiences, and admired for a legacy of imagination and innovation on and off the concert stage.

The Philadelphia Orchestra’s Triumphal Return to China

MUSIC is an internationalart,enabling people allover the world to com-municate with and understand eachother.The first cultural troupe sentby the American government to visitChina 20 years ago was the Philadel-phia Orchestra.Their perform-ances contributed greatly to Sino-American cultural exchange andpromoted friendship between theAmerican and Chinese people.InMay 1993 the Philadelphia Orches-tra came to China again as theAmerican people’s cultural

费城图书馆公司及其历史意义

费城图书馆公司是1731年由本杰明·富兰克林创办的会员图书馆。费城图书馆公司实行会员管理制度,将学术研究类书籍作为图书馆收藏的重点,为会员和非会员提供差别化的服务。费城图书馆公司的创建在美国图书馆史乃至世界图书馆史上具有举足轻重的历史地位。费城图书馆公司是图书馆史上有据可考的第一所会员图书馆,是“北美所有会员图书馆之母”,是美国民主思想与文化的重要象征,它的建立为美国民主思想的传播和民主政治的发展作出了不可替代的历史贡献。

费城染色体阴性的骨髓增殖性肿瘤患者肺动脉高压发生率、危险因素及预后分析

目的:探讨并分析费城染色体阴性的骨髓增殖性肿瘤患者肺动脉高压(PH)的发病率、影响因素和对预后的影响。方法:通过回顾性分析271例费城染色体阴性骨髓增殖性肿瘤患者的临床资料,区分不同疾病亚型分类,依据是否发生PH分为PH^(+)和PH^(-)两组,应用统计学方法,分析患者PH的发病率、危险因素和对预后的影响。结果:271例患者中PH的总体发病率为26.9%且根据疾病亚型分类后发现,原发性骨髓纤维化患者的PH发病率明显高于真性红细胞增多症患者和原发性血小板增多症患者(均P<0.05);多因素回归分析结果显示,高龄、长病程、JAK2阳性和升高的红细胞压积、乳酸脱氢酶、单核细胞计数、尿酸水平是费城染色体阴性骨髓增殖性肿瘤患者发生PH的独立危险因素(OR>1,P<0.05),且不同疾病亚型的独立危险因素存在一定的差异;生存分析结果显示,除原发性血小板增多症患者外其他类型患者中PH^(+)患者的总生存率明显低于PH~-患者(均P<0.05)。结论:PH在费城染色体阴性骨髓增殖性肿瘤患者中发病率较高,其危险因素是多样的且合并PH的患者总体生存率降低,因此,临床上应高度警惕此类患者PH的发生。

儿童费城染色体样急性淋巴细胞白血病的临床分析

目的:探讨具有治疗靶点的儿童费城染色体样急性淋巴细胞白血病(Ph-like ALL)的临床特点、分子学特征、治疗及预后。方法:2017年12月至2021年6月在苏州大学附属儿童医院初诊且具备靶向药物治疗靶点的儿童Ph-like ALL共27例,回顾性分析患儿年龄、性别、初诊时白细胞计数、遗传学特征、分子生物学改变、化疗方案、给予不同靶向药物、d 19微小残留病(MRD)、d 46 MRD、是否行造血干细胞移植(HSCT)等资料,归纳总结患儿的临床特征及治疗效果。采用Kaplan-Meier方法进行生存分析。结果:27例患儿均根据诱导缓解治疗过程中MRD水平调整化疗强度,10例在治疗过程中加用靶向药,3例患儿桥接HSCT,其中1例死亡,2例存活。24例未行HSCT患儿中,1例患儿出现复发,采用嵌合抗原受体T细胞(CAR-T)治疗后达完全缓解(CR)。27例患儿3年总生存率为(95.5±4.4)%,3年无复发生存率为(95.0±4.9)%,3年无事件生存率为(90.7±6.3)%。结论:基于MRD监测的危险度分层化疗可改善Ph-like ALL患儿预后,对化疗效果欠佳的患儿联合靶向药可尽快完全缓解,诱导缓解治疗过程中MRD持续阳性的Ph-like ALL患儿序贯CAR-T和HSCT能显著提高治疗效果。

成人复发/难治性费城染色体阳性急性淋巴细胞白血病的免疫治疗进展

酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)联合标准化疗显著提高了费城染色体阳性急性淋巴细胞白血病(Philadelphia chromosome-positive acute lymphoblastic leukemia,Ph^(+)-ALL)患者的预后,化疗联合第一代或第二代TKI治疗Ph^(+)-ALL患者的3年总生存(overall survival,OS)率为40%~60%,联合第三代TKI如帕纳替尼,其6年OS率可达75%。但是,复发/难治性Ph^(+)-ALL患者在初次挽救性治疗后2年OS率仅为20%,这需要探索新的治疗策略如免疫治疗。免疫治疗主要包括单克隆抗体的使用如贝林妥欧单抗(抗CD3和CD19双特异性抗体)、奥加伊妥珠单抗(抗CD22单克隆抗体),以及针对不同靶点的嵌合抗原受体T细胞(chimeric antigen receptor T-cell,CAR-T)疗法。然而,免疫治疗后长期生存期改善有限,一般建议患者达到完全缓解后桥接异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)。目前部分研究表明allo-HSCT能降低Ph^(+)-ALL复发率,但对基于免疫治疗后桥接alloHSCT能否改善患者OS尚存在争议,需要进一步开展研究。本篇综述将主要讨论近年来免疫治疗在成人复发/难治性Ph^(+)-ALL中的显著进展,期望为提高复发/难治性Ph^(+)-ALL患者的缓解率和改善预后提供一些帮助。

氟马替尼联合维奈克拉为基础的方案治疗费城染色体阳性白血病6例疗效分析

目的:评估氟马替尼联合维奈克拉为基础的方案治疗费城染色体阳性(Philadelphia chromosome-positive,Ph+)白血病的疗效;方法:纳入苏州大学附属第一医院血液科2021年2月至2022年4月使用氟马替尼联合维奈克拉治疗的6例费城染色体阳性急性白血病患者,回顾性分析联合方案的疗效及安全性;结果:在纳入的6例患者中,3例为初诊费城染色体阳性混合细胞白血病(Mixed phenotype acute leukemia,MPAL)患者,1例为初诊费城染色体阳性急性髓系白血病(Acute myeloid leukemia,AML)患者,1例为复发Ph+AML患者,1例为慢粒急髓变(Chronic myeloid leukemia at myeloid blastic phase,CML-MBP)患者,1例患者使用氟马替尼联合维奈克拉方案,5例患者接受氟马替尼联合维奈克拉及去甲基化药物方案;1周期后总体缓解率为100%,4例患者取得完全缓解,1例患者达到完全缓解伴血液学不完全恢复,1例患者达到形态学无白血病状态;1例患者分子学反应实现完全分子反应(Complete molecular response,CMR),3例为主要分子学反应(Major molecular response,MMR),2例未达到MMR;4例患者遗传学反应为完全细胞遗传学反应(Complete cytogenic response,CCyR);5例患者续接异基因造血干细胞移植(Allogeneic hematopoietic stem cell transplantation,allo-HSCT)。随访截止至2024年1月,5例患者仍处于缓解状态,1例患者失访。结论:氟马替尼联合维奈克拉为基础的方案治疗费城染色体阳性白血病的疗效确切,耐受性良好。

维奈克拉在急性淋巴细胞白血病中的应用和研究进展

维奈克拉是全球首个获批的高选择性口服B细胞淋巴瘤-2(B-cell lymphoma 2,Bcl-2)蛋白抑制剂,具有高亲和性的靶向肿瘤细胞凋亡的独特作用机制,目前已被美国食品药品监督管理局批准应用于治疗慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)/小淋巴细胞白血病(small lymphocytic leukemia,SLL)以及不适合接受强诱导化疗或年龄>75岁的新诊断急性髓系白血病(acute myeloid leukemia,AML)。近年来,维奈克拉在治疗急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)上也显示出其独特的优越性。对于常规治疗方案疗效不佳的特殊亚型ALL,如急性早期前体T淋巴细胞白血病(early T-cell precursor acute lymphoblastic leukemia,ETP-ALL)和ETP-ALL之外的其他复发难治性ALL(relapse/refractory ALL,R/R ALL)经维奈克拉联合化疗或其他靶向药物相较于传统疗法可获得更高的完全缓解(complete response,CR)率和长期生存率,且在费城染色体阳性的ALL(Philadelphia-chromosome positive acute lymphoblastic leukemia,Ph^(+)ALL)中联合酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)也取得了良好的效果,表明维奈克拉在ALL治疗上具有较大前景。本文就维奈克拉在ALL治疗领域的作用及研究进展展开综述。

原代Ph^(+)骨髓细胞的获取及小鼠Ph^(+)B-ALL模型的建立

目的:制备小鼠费城染色体阳性(Ph^(+))原代细胞并构建B淋巴细胞白血病(B-ALL)小鼠模型。方法:利用逆转录病毒将带有BCR-ABL P210融合基因的质粒转入C57BL/6J小鼠骨髓细胞中,输注给9 Gy总致死剂量60Coγ射线照射的同系小鼠后建立第一代Ph^(+)骨髓细胞的小鼠模型,然后获取发病小鼠脾脏和骨髓的原代细胞冻存。C57BL/6J小鼠经亚致死剂量照射后,接受第一代Ph^(+)细胞进行体内传代,顺序传代获得第三、四代Ph^(+)细胞及小鼠B-ALL模型。分别应用流式细胞术、H&E染色、外周血涂片等对建模小鼠进行免疫表型分析及病变检测。结果:输注含有P210-NGFR逆转录病毒的骨髓细胞后,小鼠出现体重明显下降、双下肢瘫痪、弓背等症状。发病小鼠的外周血涂片中可观察到原始和幼稚淋巴细胞。H&E染色结果显示,发病小鼠肝脏小叶中央静脉周围以及肝脏边缘有明显的白血病细胞浸润。流式细胞术检测结果显示,发病小鼠脾脏中CD19+NGFR+细胞随传代增加百分率逐渐升高,G1、G2和G3分别为19.0%、47.3%和61.0%。免疫表型分析结果表明,Ph^(+)细胞在B淋巴细胞中稳定传代,且随着传代增多Ph^(+)B淋巴细胞占比显著提高。结论:本研究成功制备小鼠Ph^(+)原代细胞,并顺利完成体内传代及B-ALL小鼠模型构建。

美国公共图书馆暑期学习活动的研究及启示--以费城自由图书馆“奇迹之夏”项目为例

利用网络调查法对费城自由图书馆“奇迹之夏”项目进行调查,分析项目的参与主体、服务对象、服务内容、经费来源和合作网络等内容。国内公共图书馆可以积极借鉴“奇迹之夏”的做法,加强研究,普及暑期学习理念,建立品牌,持续优化暑期学习活动的内容和形式,并积极寻求社会各界的支持与合作。

奥雷巴替尼治疗复发伴T315I突变费城染色体阳性急性淋巴细胞白血病的疗效及安全性(附5例)

目的:探索奥雷巴替尼治疗复发伴T315I突变费城染色体阳性急性淋巴细胞白血病(Philadelphia chromosome positive acute lymphoblastic leukemia,Ph^(+)ALL)患者的疗效及安全性。方法:收集该院2021年12月至2023年05月确诊复发伴T315I突变Ph^(+)ALL患者的临床资料,分析复发患者应用奥雷巴替尼后的疗效及安全性。结果:5例复发伴T315I突变Ph^(+)ALL患者应用奥雷巴替尼后,5例患者均达CR,其中3例患者达CMR、MRD(-),2例患者达CR、MRD(+)。所有患者从开始口服奥雷巴替尼到评估达CR的中位时间为37(26~58)天,复发后再次获得CR,到疾病进展或死亡或随访截止的中位PFS时间为92(47~320)天,从患者开始口服奥雷巴替尼到患者死亡或随访截止的中位OS时间为208(115~370)天。截止随访时间,2例患者处于无病存活状态、1例患者因肺部严重感染死亡、2例患者因疾病再次复发死亡。不良反应以骨髓抑制、肝功能、肾功能异常为主,未发生使患者中断治疗的不良反应。结论:奥雷巴替尼治疗伴T315I突变或复合突变的Ph^(+)ALL患者治疗效果良好且不良反应尚可耐受。

Ph阳性急性髓系白血病一例并文献复习

费城染色体(Ph染色体)阳性急性髓系白血病(Ph+AML)是一种临床罕见、生存率低、预后极差的白血病亚型,具有与慢性粒细胞白血病急髓变(CML-MBC)不同的临床及实验室特征,目前治疗尚无统一标准方案。本文报道1例经酪氨酸激酶抑制剂(TKI)、维奈克拉联合阿扎胞苷三联方案治疗获得显著疗效的Ph+AML患者,并复习相关文献,以期提高对该疾病的认识,同时为临床治疗提供参考。