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Arsenic in the treatment of newly diagnosed acute promyelocytic leukemia: current status and future research

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《医学前沿（英文）》 2011年 第5卷 第1期   页码 45-52 doi: 10.1007/s11684-011-0117-y

摘要：

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. In past decades, intensive studies on the biology and treatment of this disease have resulted in a remarkably thorough understanding of its pathogenesis and improvement of treatment outcomes. In particular, the introduction of all-trans retinoic acid to conventional chemotherapy improved dramatically the remission and survival rates of APL patients and consequently became the major treatment modality for it. In the last decade, the groundbreaking development of arsenic further improved the survival rate of APL patients. As the most active agent in APL, arsenic directly degrades the PML-RARα fusion transcript, leading to the differentiation and apoptosis of leukemia cells and the potential eradication of APL leukemia-initiating cells (LICs), thus making the disease a potentially curable type of leukemia. More notably, the recent development of oral arsenic compounds may further enhance not only clinical outcomes but also the convenience of patients, which may dramatically change the APL clinical scenario in the near future.

关键词： acute promyelocytic leukemia     arsenic     all-trans retinoic acid     survival    

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Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives

Felicitas THOL, Arnold GANSER

《医学前沿（英文）》 2010年 第4卷 第4期   页码 356-362 doi: 10.1007/s11684-010-0220-5

摘要： Acute myeloid leukemia (AML) is a very heterogeneous neoplasm of the hematopoietic stem cell. Despite important achievements in the treatment of AML, the long term survival of patients with the disease remains poor. Understanding the pathogenesis of AML better is crucial for finding new treatment approaches. During AML development hematopoietic precursor cells undergo clonal transformation in a multistep process through acquisition of chromosomal rearrangements and/or different gene mutations. Over recent years, novel gene mutations have been found in patients with AML. These mutations can be divided into two important categories, class I mutations that confer a proliferation advantage and class II mutations that inhibit myeloid differentiation. Screening for some of these mutations is now part of the initial diagnostic work-up in newly diagnosed AML patients. Information about the mutation status of specific genes is useful for risk-stratification, minimal residual disease (MRD) monitoring and increasingly also for targeted therapy, especially for patients with cytogenetically normal AML (CN-AML). Besides chromosomal rearrangements and gene mutations, epigenetic regulation of genes – meaning changes in gene expression by mechanisms other than changes in the underlying DNA sequence – also represents an important mechanism of leukemogenesis. This article reviews some of the most common mutations in CN-AML and gives a perspective of the translation of these discoveries from bench to bedside.

关键词： acute myeloid leukemia     mutations     risk stratification    

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Prognostic analysis of chronic myeloid leukemia in Chinese population in an imatinib era

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《医学前沿（英文）》 2012年 第6卷 第2期   页码 204-211 doi: 10.1007/s11684-012-0202-x

摘要：

We evaluated the outcomes of chronic myeloid leukemia (CML) patients in three clinical phases, namely, chronic (CP), accelerated (AP), and blast (BP) phases, receiving imatinib treatment. The single-institution treatment experiences of Chinese patients with CML were presented. A total of 275 CML patients (CP, 210; AP, 24; and BP, 41) who received imatinib between February 2001 and April 2008 were enrolled in this study. We evaluated the responses (hematologic, cytogenetic, and molecular), overall survival (OS), treatment event-free survival (EFS), and prognostic factors of outcome. At the cut-off point, the complete cytogenetic response (CCyR) and complete molecular response rates of patients in the CP were 84.7% and 61.9%, respectively, which were significantly higher than those of patients in the AP (50% and 29.1%, respectively, both P<0.001) and BP (24.3% and 9.7%, respectively, both P<0.001). The estimated five-year OS and five-year EFS rates were 93.2% and 86.4% for CP patients, as well as 64.5% and 50.9% for AP patients, which were significantly higher than those for BP patients (P<0.001). In CP patients, univariate analysis revealed that early treatment with imatinib, achieving CCyR within 12 months, additional cytogenetic abnormalities, and kinase domain mutations were associated with the treatment outcome. More patients are needed to carry out multivariate analysis.

关键词： imatinib     chronic myeloid leukemia     complete cytogenetic response    

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FGF13 suppresses acute myeloid leukemia by regulating bone marrow niches

《医学前沿（英文）》 2022年 第16卷 第6期   页码 896-908 doi: 10.1007/s11684-022-0944-z

摘要： Fibroblast growth factor 13 (FGF13) is aberrantly expressed in multiple cancer types, suggesting its essential role in tumorigenesis. Hence, we aimed to explore its definite role in the development of acute myeloid leukemia (AML) and emphasize its associations with bone marrow niches. Results showed that FGF13 was lowly expressed in patients with AML and that its elevated expression was related to prolonged overall survival (OS). Univariate and multivariate Cox regression analyses identified FGF13 as an independent prognostic factor. A prognostic nomogram integrating FGF13 and clinicopathologic variables was constructed to predict 1-, 3-, and 5-year OS. Gene mutation and functional analyses indicated that FGF13 was not associated with AML driver mutations but was related to bone marrow niches. As for immunity, FGF13 was remarkably associated with T cell count, immune checkpoint genes, and cytokines. In addition, FGF13 overexpression substantially inhibited the growth and significantly induced the early apoptosis of AML cells. The xenograft study indicated that FGF13 overexpression prolonged the survival of recipient mice. Overall, FGF13 could serve as an independent prognostic factor for AML, and it was closely related to the bone marrow microenvironment.

关键词： acute myeloid leukemia     FGF13     prognosis     immune-related genes     bone marrow niches    

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hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia

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《医学前沿（英文）》 2015年 第9卷 第3期   页码 304-311 doi: 10.1007/s11684-015-0400-4

摘要：

In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n?=?33) and allo-HSCT (n?=?60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P<0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P<0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2therapy were predictors of poor overall survival, whereas hemoglobin<100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

关键词： chronic myeloid leukemia     imatinib     dasatinib     nilotinib     allogeneic hematopoietic stem cell transplantation    

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Molecular mechanisms of leukemia-associated protein degradation

Ying-Li WU, Guo-Qiang CHEN, Hu-Chen ZHOU,

《医学前沿（英文）》 2010年 第4卷 第4期   页码 363-370 doi: 10.1007/s11684-010-0210-7

摘要： Chemical biology, using small molecules as probes to study the cellular signaling network, has developed rapidly in recent years. The interaction between chemistry and biology not only provides new insight into the understanding of cellular activities, but also generates new lead compounds for the treatment of diseases. Transcription factors and kinases such as retinoic acid receptor-alpha (RARα), acute myeloid leukemia 1 (AML1), CAAT/enhancer-binding protein α (C/EBPα), c-myc, and c-abl play important roles in the differentiation of hematopoietic stem/progenitor cells. Abnormalities in these proteins may cause the dysregulation of hematopoiesis and even the occurrence of leukemia. Ubiquitin-mediated protein degradation represents a critical mechanism in regulating the cellular levels and functions of these proteins. Thus, targeting protein degradation has been emerging as an important strategy to conquer malignant diseases. In this review, we will summarize the recent advances in the understanding of the roles of protein degradation in leukemia, with an emphasis on the mechanisms revealed by small molecules.

关键词： protein degradation     leukemia     chemical biology     transcription factors     oncoprotein    

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Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

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《医学前沿（英文）》 2012年 第6卷 第4期   页码 416-420 doi: 10.1007/s11684-012-0224-4

摘要：

Acute lymphoblastic leukemia includes T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL). In children, T-ALL usually has a worse prognosis than B-ALL, although childhood T-ALL prognoses have improved remarkably. The varying outcomes among T-ALL cases suggest that an unrecognized biological heterogeneity may contribute to chemo-resistance. Deep exploration of T-lymphocyte development in recent years has found a subgroup of patients with a phenotype that resembles early T-cell precursor, which confers a much poorer prognosis than any other form of T-ALL. This novel subtype of T-ALL was called early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Flow cytometry data from T-ALL patients enrolled in Shanghai Children’s Medical Center between July 2002 and October 2010 were assessed according to Dr. Campana’s protocol. Among total 89 T-ALL cases, 74 cases had enough immunophenotype data available to differentiate between ETP (CD1a-, CD8-, CD5dim, at least one marker of stem cell or myeloid lineage) and non-ETP. From these 74 subjects, 12 ETP-ALL cases (16.2%) were identified. The event-free survival (EFS) rate at 66.8 months was 11.1%±10.1% for ETP-ALL and 57.6%±5.6% for non-ETP-ALL (P=0.003). The overall survival rates were 13.3%±11.0% for ETP-ALL and 64.7%±6.3% for non-ETP-ALL (P=0.002). Our findings demonstrate that early T-cell precursor leukemia is a very high-risk subtype of acute lymphoblastic leukemia with poor prognosis.

关键词： acute lymphoblastic leukemia     early T precursor     prognosis    

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methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia

null

《医学前沿（英文）》 2015年 第9卷 第4期   页码 412-420 doi: 10.1007/s11684-015-0423-x

摘要：

Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With the rapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk.

关键词： preleukemic stem cell     acute myeloid leukemia     relapse     DNMT3A    

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Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese

《医学前沿（英文）》 2023年 第17卷 第3期   页码 518-526 doi: 10.1007/s11684-022-0958-6

摘要： Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08–2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12–18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

关键词： acute lymphoblastic leukemia     child     venous thromboembolism     epidemiology     clinical characteristic     risk factor    

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unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia

《医学前沿（英文）》 2021年 第15卷 第5期   页码 728-739 doi: 10.1007/s11684-021-0833-x

摘要： Relapse is the main problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcome of a second allo-HSCT (HSCT2) for relapse post-HSCT has shown promising results in some previous studies. However, little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia (AL) post-chemotherapy plus modified donor lymphocyte infusion (post-Chemo+m-DLI) after the first allo-HSCT (HSCT1). Therefore, we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo+m-DLI in our center. With a median follow-up of 918 (457–1732) days, 26 patients (92.9%) achieved complete remission, and 2 patients exhibited persistent disease. The probabilities of overall survival (OS) and disease-free survival (DFS) 1 year after HSCT2 were 25.0% and 21.4%, respectively. The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1%±4.9% and 25.0%±8.4%. The cumulative incidences of relapse were 50.0%±9.8% and 53.5%±9.9% at 1 and 2 years post-HSCT2, respectively. Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2, and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2. Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo+m-DLI.

关键词： second hematopoietic stem cell transplantation     acute leukemia     relapse     chemotherapy     modified donor lymphocyte infusion    

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ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/-catenin signaling

《医学前沿（英文）》 2023年 第17卷 第4期   页码 685-698 doi: 10.1007/s11684-022-0942-1

摘要： Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

关键词： acute myeloid leukemia     acyl-CoA synthetase long chain family member 5     Wnt3a     palmitoylation     ABT-199    

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Management of mantle cell leukemia with cardiac involvement leading to cardiogenic shock

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《医学前沿（英文）》 2014年 第8卷 第2期   页码 254-258 doi: 10.1007/s11684-014-0319-1

摘要：

Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage of the disease and generally associated with extensive extra-nodal involvement. Pericardial invasion has been reported, however we could not find a report of myocardial infiltration by this disease since the appraisal of the term “mantle cell lymphoma” in 1992. Here we report a case of cardiac involvement by mantle cell leukemia leading to cardiogenic shock which complicates the treatment decisions.

关键词： mantle cell lymphoma     bendamustine     cardiogenic shock    

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CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia

《医学前沿（英文）》 2022年 第16卷 第1期   页码 139-149 doi: 10.1007/s11684-021-0835-8

摘要： The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia     bispecific antibody     trispecific antibody     CD19     CD20    

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AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches

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《医学前沿（英文）》 2012年 第6卷 第3期   页码 248-262 doi: 10.1007/s11684-012-0206-6

摘要：

The AML1-ETO fusion transcription factor is generated by the t(8;21) translocation, which is present in approximately 4%–12% of adult and 12%–30% of pediatric acute myeloid leukemia (AML) patients. Both human and mouse models of AML have demonstrated that AML1-ETO is insufficient for leukemogenesis in the absence of secondary events. In this review, we discuss the pathogenetic insights that have been gained from identifying the various events that can cooperate with AML1-ETO to induce AML in vivo. We also discuss potential therapeutic strategies for t(8;21) positive AML that involve targeting the fusion protein itself, the proteins that bind to it, or the genes that it regulates. Recently published studies suggest that a targeted therapy for t(8;21) positive AML is feasible and may be coming sometime soon.

关键词： AML1-ETO     mouse model     leukemia     t(8     21)     pathway hits     mutation     hematopoiesis     Kasumi-1     CD34+    

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Philadelphia chromosome-positive acute myeloid leukemia with masses and osteolytic lesions: finding of

null

《医学前沿（英文）》 2017年 第11卷 第3期   页码 440-444 doi: 10.1007/s11684-017-0523-x

摘要：

Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lytic lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lytic bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type (de novo or blast crisis) remained unclear.

关键词： Philadelphia chromosome     acute myeloid leukemia     mass     osteolysis     positron emission tomography    

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标题 作者 时间 类型 操作

Arsenic in the treatment of newly diagnosed acute promyelocytic leukemia: current status and future research

null

期刊论文

Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives

Felicitas THOL, Arnold GANSER

期刊论文

Prognostic analysis of chronic myeloid leukemia in Chinese population in an imatinib era

null

期刊论文

FGF13 suppresses acute myeloid leukemia by regulating bone marrow niches

期刊论文

hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia

null

期刊论文

Molecular mechanisms of leukemia-associated protein degradation

Ying-Li WU, Guo-Qiang CHEN, Hu-Chen ZHOU,

期刊论文

Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

null

期刊论文

methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia

null

期刊论文

Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese

期刊论文

unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia

期刊论文

ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/-catenin signaling

期刊论文

Management of mantle cell leukemia with cardiac involvement leading to cardiogenic shock

null

期刊论文

CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia

期刊论文

AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches

null

期刊论文

Philadelphia chromosome-positive acute myeloid leukemia with masses and osteolytic lesions: finding of

null

期刊论文