LATS1 Promotes B-ALL Tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation pattern.The specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently unclear.Thus,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.Methods The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis experiments.Gene expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.Results Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels.YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 cells.Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase.Before and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 phosphorylation.Further,YAP1 was distributed in the plasma.Conclusion LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

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).

Donor-derived CD 19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD 19-positive B-ALL after Allogeneic Hematopoietic Stem Cell Transplantation

Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Focal lymphoblastic transformation of chronic myelogenous leukemia develops into erythroid leukemia:A case report

BACKGROUND We present a case of focal lymphoblastic transformation to erythroid leukemia following acute myeloblastic transformation in a patient with chronic myelogenous leukemia(CML)and discuss its mechanism of occurrence and development.CASE SUMMARY The presence of the Philadelphia(Ph)chromosome was identified through karyotype analysis,while the BCR-ABL fusion gene was detected using quantitative real-time polymerase chain reaction of the peripheral blood sample.Fluorescence in situ hybridization was used to detect the expression of the BCRABL gene in the lymphoma.Antigen expression and gene mutations in the primitive cells were detected by flow cytometry.The analysis confirmed the presence of CML along with focal lymphoblastic transformation to erythroid leukemia.Additionally,the patient was found to have secondary erythroid leukemia,along with multiple new gene mutations and abnormalities in complex karyotypes of chromosomes.CONCLUSION Our findings suggest a possible molecular basis for the focal lymphoblastic transformation secondary to myeloblastic transformation in patients with CML.

Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis

BACKGROUND Asparaginase(ASP)is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia(ALL);ASP-associated pancreatitis(AAP)is the main adverse reaction of ASP.Recurrent pancreatitis is a complication of AAP,for which medication is ineffective.AIM To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography(ERCP)in treating recurrent pancreatitis due to AAP.METHODS From May 2018 to August 2021,ten children(five males and five females;age range:4–13 years)with AAP were treated using ERCP due to recurrent pancreatitis.Clinical data of the ten children were collected,including their sex,age,weight,ALL risk grading,clinical symptoms at the onset of pancreatitis,time from the first pancreatitis onset to ERCP,ERCP operation status,and postoperative complications.The symptomatic relief,weight change,and number of pancreatitis onsets before and after ERCP were compared.RESULTS The preoperative symptoms were abdominal pain,vomiting,inability to eat,weight loss of 2-7 kg,and 2-9 pancreatitis onsets.After the operation,nine of ten patients did not develop pancreatitis,had no abdominal pain,could eat normally;the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP,but eating was not affected.The postoperative weight gain was 1.5-8 kg.There was one case of post ERCP pancreatitis and two cases of postoperative infections;all recovered after medication.CONCLUSION ERCP improved clinical symptoms and reduced the incidence of pancreatitis,and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

The Role of Mitochondrial VDAC2 in the Survival and Proliferation of T-Cell Acute Lymphoblastic Leukemia Cells

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC50 = 3.943 μM) and Molt4 (IC50 = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC50. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.

Comparison of the Effects of L-asparaginase and Pegaspargase in the Treatment of Adult Acute Lymphoblastic Leukemia

Objective:To compare the effect of L-asparaginase and pegaspargase in the treatment of adult acute lymphoblastic leukemia.Methods:In this study,96 patients who received treatment at the Shaanxi Provincial People’s Hospital from April 2019 to April 2021 were selected.The control group received L-asparaginase treatment,and the observation group received pegaspargase treatment.The curative effect and adverse reaction rate were compared between the two groups.Results:Comparing the experimental statistical results of the observation and the control groups,it can be concluded that the effect of the former group is better than that of the latter group in terms of clinical curative effect and statistics of adverse reactions.Conclusion:In the treatment of adult acute lymphoblastic leukemia,the application of pegaspargase therapy has a significantly better clinical effect and is worthy of further promotion.

Macrophage Activation Syndrome in a Context of Pre-B Type Lymphoblastic Acute Leucemia: A Case Report

Macrophage activation syndrome (MAS) is linked to inappropriate stimulation of macrophage cells in the bone marrow and lymphoid system, resulting in abnormal phagocytosis of figurative blood elements and the release of pro-inflammatory cytokines. It is a rare and serious hyper-inflammatory condition of diagnostic and therapeutic emergency. MAS is characterized by non-specific clinical and laboratory signs associated with images of hemophagocytosis. MAS is either “primary” (familial or pediatric forms), or “secondary/reactive” to infection, neoplasia, or autoimmune disease. Hemopathies dominate MAS secondary to neoplasia. B-type acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the proliferation and accumulation of B lymphoid progenitors, blocked at an early stage of differentiation, leading to suppression of polyclonal hematopoiesis and subsequent development of signs associated with bone marrow failure. In this context, we report the observation of a macrophage activation syndrome (MAS) associated with ALL, diagnosed at Hôpital Principal de Dakar/Senegal, in a 69-year-old patient with a well-controlled type 2 diabetes under oral antidiabetic therapy (OAD) and good general condition.

β_2微球蛋白 白细胞介素-2 白细胞介素-6 在急性淋巴细胞白血病合并中枢神经系统白血病患儿脑脊液中的变化及其意义

目前,急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）已成为儿科常见急症之一,极大侵害广大婴幼儿的身体健康,威胁他们的生命安全。随着医学技术的进步,ALL缓解率不断得到提高,但该病致病机制较复杂,特别是部分合并中枢神经系统白血病（central nervous system leukemia,CNSL）患儿出院后,

儿童急性淋巴细胞白血病复发机制的研究进展

儿童急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）目前化疗治愈率达85%,复发仍然是导致治疗失败的最常见原因,发生率约20%[1]。复发后患儿长期生存率明显降低,约40%[2],因此与ALL复发相关的研究仍在不断探索中,复发机制尚未明确：本文将结合国内外文献对复发机制的研究进展做一综述。

谷胱甘肽转移酶P1基因多态性与儿童急性白血病易感性关系的研究进展

急性白血病（acute leukemia,AL）是儿童三大恶性肿瘤之一,占其总发病率的近80%,急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）又是儿童AL中最常见的一种类型,其发病率约占儿童恶性肿瘤的25%-30%。尽管儿童AL在临床上十分常见,治疗水平及治愈率均有显著提高,但其发病因素仍不十分清楚,仅有约小于5%的病例可进行危险因素的预测。

儿童颞骨乳突B淋巴母细胞淋巴瘤1例

1临床资料患儿,男,9岁,主因间断右侧口角歪斜1月余,加重伴耳痛3天于2019-05-28入院。患儿入院前1月余无明显诱因间断出现右侧口角歪斜,伴右眼偏斜,偶伴右耳疼痛,每次持续约20~100 min,可自行恢复正常,病情间断反复发作,无发热、头痛、头晕及眩晕,无张口受限,无耳溢液及听力下降,曾就诊于神经内科,诊断不详,予营养神经等治疗后病情无缓解。入院前3天患儿无明显诱因口角歪斜呈持续性,伴右侧耳痛,门诊考虑“右侧周围性面神经麻痹待查;右侧中耳乳突炎”收治入院。患儿既往体健,家族中无遗传性疾病史。专科查体:右侧额纹消失,右眼闭合不全,无溢泪,右侧鼻唇沟变浅,口角对称,张口时口角左偏,伸舌无偏斜;双侧耳廓无畸形,右侧外耳道变窄、后壁肿胀,鼓膜不能窥及;右侧乳突区压痛;鼓腮漏气;左耳(-)。面神经检测未见异常。颞骨CT示右侧中耳鼓室及乳突小房渗出性病变,未见骨质破坏(图1A)。

儿童急性淋巴细胞白血病中枢神经系统白血病早期诊断研究

急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）发病率约占儿童肿瘤的1/4,占儿童白血病75%～80%。随着分子生物学技术及对疾病治疗研究的不断进步,疾病的预后也得到很大的改善。

儿童急性淋巴细胞白血病复发与分子遗传学相关性研究

儿童急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）缓解后仍有约20%的患儿复发,复发后即使进行高强度化疗、免疫治疗及造血干细胞移植等治疗,长期无病生存的结果仍不尽人意,仅30%~40%的患儿可被治愈。

CYP1A1基因多态性与急性白血病易感性关系的研究进展

急性白血病是一类造血干细胞发生恶性克隆的疾病,是儿童最常见的恶性肿瘤,而急性淋巴细胞性白血病（acute lymphoblastic leukemia,ALL）是导致儿童死亡的主要原因之一。以往研究认为ALL的发生可能与射线、饮食及环境致癌物接触史等因素有关,然而,即使相似的生活方式或致癌物暴露史个体间ALL易感性仍存在较大差异。因此,目前大量学者已转向前致癌物代谢酶基因的相关性研究。

Resveratrol Induces Apoptosis and Autophagy in T-cell Acute Lymphoblastic Leukemia Cells by Inhibiting Akt/mTOR and Activating p38-MAPK

Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.

CD20阳性Ph阴性成人急性前B淋巴细胞白血病1例并文献复习

大多数成熟急性B淋巴细胞白血病（B-lineage acute lymphoblastic leukemia,B-ALL）表达CD20分子,只有30%-50%的急性前B细胞白血病（B-cell precursor-acute lymphoblastic leukemia,BCP-ALL）幼稚细胞表达CD20。CD20阳性对BCP-ALL预后的影响多在儿童中讨论,但无定论。现将报道1例成人CD20阳性Ph阴性BCP-ALL,并复习相关文献,

Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis

Objective： The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation （AHSCT） in the treatment of lymphoblastic lymphoma （LL）. Methods： We relxospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation （HSCT） from December 1989 to December 2009 in a single institution. Results： HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months （range, 24.6-173.1 months）. The 5-year overall survival （OS） and event-free survival （EFS） rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow （BM） involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. Conclusions These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission （CR1）.

Decitabine for Relapsed Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse after allogeneic hematopoietic stem cell transplantation（allo-HSCT） remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine（DAC） for treating patients with acute lymphoblastic leukemia（ALL） who relapsed after allogeneic hematopoietic stem cell transplantation（allo-HSCT）. We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy. Nine patients received DAC combined with chemotherapy and donor stem cell infusion, and 3 patients received single-agent DAC. Ten of the 12 patients achieved complete remission（CR）, 1 achieved a partial remission（PR）, and 1 had no response（NR） after treatment at the latest follow-up（LFU）, the median survival was 11.2 months（range, 3.8–34, 7 months）. The 1-and 2-year overall survival（OS） rates were 50%（6/12） and 25%（3/12）, respectively. Five patients were still alive; 4 had maintained CR and 1 was alive with disease. Patients with Philadelphia chromosome-positive ALL had higher survival rate than patients with Philadelphia chromosome-negative ALL（57.1% vs. 20%）. No aggravated flares of graft-versus-host disease（GVHD） were observed during DAC treatment. Therefore, DAC may be a promising therapeutic agent for ALL recurrence after allo-HSCT.