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Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a disease in which too many immature granulocytes (a type of white blood cell) are found in the blood and bone marrow. There are a number of subtypes of AML including acute myeloblastic leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, erythroleukemia, and acute megakaryoblastic leukemia.

(UK spelling: Leukaemia)

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Latest Research Publications
Childhood AML
Molecular Genetics of AML

Information Patients and the Public (10 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Riyahi N, Safaroghli-Azar A, Sheikh-Zeineddini N, et al.
Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.
Cancer Invest. 2019; 37(7):311-324 [PubMed] Related Publications
Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.

Guo Y
Clinical significance of serum MicroRNA-203 in patients with acute myeloid leukemia.
Bioengineered. 2019; 10(1):345-352 [PubMed] Related Publications
This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.

Wei AH, Roberts AW
Polyclonal Heterogeneity: The New Norm for Secondary Clinical Resistance to Targeted Monotherapy in Relapsed Leukemia?
Cancer Discov. 2019; 9(8):998-1000 [PubMed] Related Publications
In this issue, McMahon and colleagues demonstrate that secondary clinical resistance to the FLT3 inhibitor gilteritinib in relapsed acute myeloid leukemia is often polyclonal and commonly mediated by heterogeneous mutations that activate downstream RAS-MAPK pathways. These findings and recent data from others indicate that emergence of multiple clones, each with distinct mechanisms of resistance, is a common finding at secondary failure of single-agent-targeted therapies for relapsed leukemias.

Wang J, Chen R, Lin X, et al.
New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: A case report.
Medicine (Baltimore). 2019; 98(30):e16586 [PubMed] Related Publications
RATIONALE: Acute myeloid leukemia (AML), in patients with coronary heart disease (CHD) and treated percutaneous coronary intervention (PCI), is rarely seen in clinic. There are few similar cases reported, and there are no evidence-based medicine guidelines for the treatment.
PATIENT CONCERNS: A 52-year-old man was diagnosed with coronary atherosclerotic heart disease in November 2011, and received a stent placement in the left anterior descending coronary artery 1 year later. One day after the surgery, his laboratory tests showed pancytopenia.
DIAGNOSES: Based on precise diagnosis of leukemia, namely cell morphology, immunology, cytogenetics, and molecular biological typing, the patient was diagnosed with AML-M2.
INTERVENTIONS: The patient received idarubicin with cytarabine in 1st cycles, and single cytarabine regimen was used in 2nd and 3rd cycles for the accumulative toxicity of idarubicin in postinduction chemotherapy. Meanwhile, staged-treatment strategy was implemented by using antiplatelet drugs during different chemotherapy phases, and personalized pharmaceutical care on the basis of the recognition of potential adverse effects of chemotherapy regimen.
OUTCOMES: Until now, the disease-free survival in the patient has been over 6 years, and he is still followed up in clinic.
LESSONS: Although leukemia accompanied with coronary heart disease, even after receiving the coronary stenting therapy is rarely seen in clinic, the treatment with antiplatelet drugs for post chemotherapy patients with coronary disease is necessary. Clinical pharmacists are supposed to be more proficient in developing personalized drug treatment strategies, especially maintaining the balance between the effect and the risk in difficult and complex cases.

Chunxia D, Meifang W, Jianhua Z, et al.
Tobacco smoke exposure and the risk of childhood acute lymphoblastic leukemia and acute myeloid leukemia: A meta-analysis.
Medicine (Baltimore). 2019; 98(28):e16454 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Tobacco smoke contains carcinogens known to damage somatic and germ cells. In this study, we investigated the effect of tobacco smoking on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML).
METHODS: Information about tobacco smoking exposures of the mother before, during, and after pregnancy was collected via PubMed, Embase, and Web of Science databases through November 5, 2018. We performed to evaluate the association between smoking exposure and the risk of childhood ALL and AML. Study selection, data abstraction, and quality assessment were performed by 2 independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: Nineteen case-control studies of childhood leukemia (age < 15 years) conducted in 9 countries from 1974 to 2018. Maternal smoking exposures did not a significant association with childhood ALL (OR = 1.004, 95% CI 0.953-1.058, P = .881) and AML (OR = 0.92, 95% CI 0.815-1.038, P = .177) during exposure time windows. However, there was an association with paternal smoking and ALL (OR = 1.15, 95% CI 1.038-1.275, P = .007). Paternal smoking in AML showed there was no association with smoking exposures and childhood AML (OR = 1.133, 95% CI 0.943-1.362, P = .181). Next, maternal daily cigarettes consumption showed no associations with ALL (OR = 1.08, 95% CI 1.000-1.168, P = .051) during pregnancy. No association with maternal daily smoking and AML (OR = 0.909, 95% CI 0.682-1.211, P = .514). Paternal daily cigarettes consumption was associated with increased risks of childhood ALL (OR = 1.200, 95% CI 1.112-1.302, P = .000). The higher consumption of paternal smoking (more than 10 per day) was significantly related to childhood ALL. Paternal daily smoking consumption also was related to AML (OR = 1.242, 95% CI 1.031-1.496, P = .022).
CONCLUSION: Maternal smoking before, during, or after pregnancy was not associated with childhood ALL or AML. However, paternal smoking was related to a significantly elevated risk of childhood ALL during pregnancy, but not for AML. Maternal daily smoking consumption was not associated with ALL or AML during pregnancy. The higher consumption of paternal smoking were, the higher the risk of childhood ALL or AML.

Savona MR, Rathmell JC
Mitochondrial Homeostasis in AML and Gasping for Response in Resistance to BCL2 Blockade.
Cancer Discov. 2019; 9(7):831-833 [PubMed] Related Publications
Understanding resistance to BCL2 inhibition is a critical scientific and clinical challenge. In this issue of

Boileau M, Shirinian M, Gayden T, et al.
Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness.
Nat Commun. 2019; 10(1):2891 [PubMed] Free Access to Full Article Related Publications
Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.

Rodríguez-Veiga R, Montesinos P, Boluda B, et al.
Incidence and outcome of invasive fungal disease after front-line intensive chemotherapy in patients with acute myeloid leukemia: impact of antifungal prophylaxis.
Ann Hematol. 2019; 98(9):2081-2088 [PubMed] Related Publications
Few reports analyze the incidence and clinical outcome of invasive fungal disease (IFD) in patients with newly diagnosed acute myeloid leukemia (AML) undergoing intensive chemotherapy, and thus the impact of different antifungal prophylactic regimens remains unclear. We analyze the incidence and clinical outcome of IFD in a large series of adult AML patients undergoing front-line intensive induction and consolidation chemotherapy between 2004 and 2015 in a single institution. Three antifungal prophylaxis regimens were given (2004-2005 oral fluconazole, 2006-2012 intravenous itraconazole, and 2013-2015 voriconazole). Overall, 285 patients and 589 intensive chemotherapy episodes were assessed (47%) (induction courses 47% and consolidation 53%). The median age was 51 years (range, 17-65). We observed 56 (10%) episodes of IFD. According to the EORTC 2008 criteria, IFD was classified as possible (29, 52%), probable (17, 30%), and proven (10, 18%). Possible/probable/proven IFD rate was significantly lower during HiDAC consolidation as compared to any anthracycline-containing chemotherapy courses (2% vs. 11%, P = 0.001), and under voriconazole prophylaxis as compared to itraconazole and fluconazole (6% vs. 11% vs. 15%, P = 0.007), and the multivariate analysis showed that they were independent risk factors. Patients under voriconazole prophylaxis had shorter hospitalization duration and less frequent use of empirical or directed antifungal therapy. In conclusion, IFD was a frequent complication during upfront intensive chemotherapy courses for adult AML patients. This retrospective study shows that voriconazole prophylaxis was feasible and associated with a lower risk of IFD compared with intravenous itraconazole or oral fluconazole schedules.

Chen KTJ, Gilabert-Oriol R, Bally MB, Leung AWY
Recent Treatment Advances and the Role of Nanotechnology, Combination Products, and Immunotherapy in Changing the Therapeutic Landscape of Acute Myeloid Leukemia.
Pharm Res. 2019; 36(9):125 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is the most common acute leukemia that is becoming more prevalent particularly in the older (65 years of age or older) population. For decades, "7 + 3" remission induction therapy with cytarabine and an anthracycline, followed by consolidation therapy, has been the standard of care treatment for AML. This stagnancy in AML treatment has resulted in less than ideal treatment outcomes for AML patients, especially for elderly patients and those with unfavourable profiles. Over the past two years, six new therapeutic agents have received regulatory approval, suggesting that a number of obstacles to treating AML have been addressed and the treatment landscape for AML is finally changing. This review outlines the challenges and obstacles in treating AML and highlights the advances in AML treatment made in recent years, including Vyxeos®, midostaurin, gemtuzumab ozogamicin, and venetoclax, with particular emphasis on combination treatment strategies. We also discuss the potential utility of new combination products such as one that we call "EnFlaM", which comprises an encapsulated nanoformulation of flavopiridol and mitoxantrone. Finally, we provide a review on the immunotherapeutic landscape of AML, discussing yet another angle through which novel treatments can be designed to further improve treatment outcomes for AML patients.

Bell CC, Fennell KA, Chan YC, et al.
Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.
Nat Commun. 2019; 10(1):2723 [PubMed] Free Access to Full Article Related Publications
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.

Minuesa G, Albanese SK, Xie W, et al.
Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Nat Commun. 2019; 10(1):2691 [PubMed] Free Access to Full Article Related Publications
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

Ye J, Luo D, Yu J, Zhu S
Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia.
Hematology. 2019; 24(1):487-491 [PubMed] Related Publications
OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied.
METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets.
RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network.
CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.

Yanada M, Mori J, Aoki J, et al.
Allogeneic hematopoietic cell transplantation for patients with a history of multiple relapses of acute myeloid leukemia.
Ann Hematol. 2019; 98(9):2179-2186 [PubMed] Related Publications
The prognosis of patients with acute myeloid leukemia (AML) is dismal after experiencing multiple relapses. This study retrospectively analyzed outcomes of allogeneic hematopoietic cell transplantation (HCT) for 192 adults with AML in third or subsequent complete remission (CR3+), 300 in second relapse (REL2), and 50 in third or subsequent relapse (REL3+) who were enrolled in a Japanese nationwide transplantation registry. The study population included patients undergoing umbilical cord blood transplantation, but not those undergoing haploidentical HCT. Patients transplanted in CR3+ had better survival than those transplanted in REL2 and REL3+ (48%, 21%, and 12% at 4 years; P < 0.001), and this was due to a reduction in post-transplant relapse (23%, 57%, and 52%; P < 0.001). The corresponding cumulative incidence of non-relapse mortality was 33%, 26%, and 36% (P = 0.022). Multivariate analysis revealed significantly lower relapse and overall mortality for those in CR3+ and significantly lower non-relapse mortality for those in REL2. Hazard ratios (95% confidence intervals) for overall mortality were 2.02 (1.56-2.64) for REL2+ versus CR3+ (P < 0.001) and 2.12 (1.40-3.19) for REL3+ versus CR3+ (P < 0.001). Our analysis demonstrates the curative potential of allogeneic HCT for patients with a history of multiple AML relapses and suggests the potential benefits and risks of reinduction attempt before transplantation, highlighting the need for an individualized approach in determining whether to give reinduction therapy in this setting.

Ye P, Pei R, Jin J, et al.
Modified cladribine, cytarabine, and G-CSF as a salvage regimen in patients with relapsed/refractory acute myeloid leukemia: a bridge to myeloablative allogeneic hematopoietic stem cell transplantation.
Ann Hematol. 2019; 98(9):2073-2080 [PubMed] Related Publications
Patients with primary refractory or early relapsed acute myeloid leukemia (AML) have a dismal prognosis, and the treatment options for these patients are limited. The present study retrospectively examined the efficacy and toxicities of the combination of cladribine 5 mg/m

Dereń-Wagemann IE, Kuliczkowski K
Significance of apoptosis and autophagy of leukemic blasts for the outcomes of acute myeloid leukemia patients.
Adv Clin Exp Med. 2019; 28(7):861-869 [PubMed] Related Publications
BACKGROUND: Cytostatic treatment induces apoptosis or other types of cell death like autophagy, necrosis, mitotic catastrophe, etc. Autophagy can play a role in the drug resistance of neoplastic cells, allowing the survival of blast cells under stressful conditions, such as the use of cytostatics. Studies on apoptosis and autophagy 12-24 h after the start of treatment have not been conducted until now.
OBJECTIVES: The study aimed to investigate the predictive and prognostic significance of autophagy and apoptosis in patients with acute myeloid leukemia (AML).
MATERIAL AND METHODS: The study included 38 patients. Blood was collected before and 12-24 h after the start of treatment, since at that time point, the appropriate blast cell count was still available. Autophagy was measured with the expression of the ATG5, MAP1L3, LC3-I, and LC3-II proteins. The percentage of mononuclear cells in early and late apoptosis was evaluated with flow cytometry, using the annexin V and propidium iodide (PI) binding assay.
RESULTS: The percentage of apoptotic blast cells before treatment was not associated with the response. However, in the remission group, the overall percentage of apoptotic cells measured 12-24 h after the start of treatment was higher than in non-remission patients, which was statistically significant. In neither group we found any difference in the level of autophagy before and 12-24 h after the start of treatment. Nevertheless, we observed an increasing tendency of the MAP1LC3 protein expression (not statistically significant) in the remission group 12-24 h after the start of treatment. Patients with a higher percentage of blast cells in apoptosis and with a higher expression of MAP1LC3 protein measured 12-24 h after the start of the therapy had longer overall survival (OS).
CONCLUSIONS: A higher percentage of apoptotic as well as autophagic blast cells measured 12-24 h after the start of the chemotherapy is an independent factor associated with better outcomes.

Ram R, Amit O, Zuckerman T, et al.
Venetoclax in patients with acute myeloid leukemia refractory to hypomethylating agents-a multicenter historical prospective study.
Ann Hematol. 2019; 98(8):1927-1932 [PubMed] Related Publications
Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.

Farnaby W, Koegl M, Roy MJ, et al.
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nat Chem Biol. 2019; 15(7):672-680 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

Cao T, Ye Y, Liao H, et al.
Relationship between CXC chemokine receptor 4 expression and prognostic significance in acute myeloid leukemia.
Medicine (Baltimore). 2019; 98(23):e15948 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
CXC chemokine receptor 4 (CXCR4) expression on acute myeloid leukemia (AML) cells correlated with stromal cell derived factor-1α (SDF-1α) and retained hematopoietic progenitors and leukemia cells within the bone marrow microenvironment. Here, we examined CXCR4 expression in 134 de novo AML and 21 controls by flow cytometry, evaluated the relationship between CXCR4 expression and clinical characteristics, and elucidated the prognostic significance of CXCR4 expression in AML prospectively. We found that the CXCR4 expression was significantly higher in AML patients than controls (P = .000). One hundred thirty four cases of de novo AML patients were divided into 2 groups according to the median of CXCR4 relative fluorescence intensity (RFI). CXCR4 high group (RFI >4.23) had markedly shorter overall survival (OS) and disease-free survival (DFS) than CXCR4 low group (RFI ≤4.23) in 106 AML patients who received chemotherapy (P = .002; .026, respectively). Furthermore, in the 87 non-M3 patients who received induction therapy, there was a significant decrease for OS but not for DFS in the CXCR4 high group (P = .047 and .178, respectively). Moreover, high levels of CXCR4 expression independently increased the risk of relapse in both all AML and non-M3 patients who achieved complete remission (CR) after chemotherapy (odds ratio = 1.090, P = .010; odds ratio = 1.068, P = .048, respectively). Collectively, our data suggest that CXCR4 overexpression was an independent prognostic factor for disease relapse and poorer OS in both all AML and non-M3 patients. CXCR4 expression levels can be determined at disease presentation by the flow rapidly and easily. As such, CXCR4 could be used as a potential therapeutic target in AML patients with poor prognosis.

Capo-Chichi JM, Michaels P, Tremblay-Le May R, et al.
Emerging patterns in clonal haematopoiesis.
J Clin Pathol. 2019; 72(7):453-459 [PubMed] Related Publications
Clonal haematopoiesis (CH) is defined by the presence of acquired mutations and/or cytogenetic abnormalities in haematopoietic cells. By definition, these premalignant clones do not meet criteria for haematopoietic neoplasms listed in the Revised Fourth Edition of the WHO classification. CH is fairly common in elderly individuals and is associated with higher risks for haematological cancers, in particular myelodysplastic syndrome and acute myeloid leukaemia (AML), as well as cardiovascular events. Similar small clones have also been detected during follow-up in patients with AML in morphological remission, in individuals with aplastic anaemia, and in pre-chemotherapy blood samples from patients with other types of cancers. In each of these contexts, the presence of mutations carries different clinical implications, and sometimes demonstrates unique genetic profiles. Emerging research suggests that the number and identity of mutations, the size of the mutant clones and various other factors, including age, immune status and history of exogenous drugs/toxins, are important for disease biology and progression. This review focuses specifically on the subset of CH with gene mutations detected by sequencing, and includes discussions of nomenclature and molecular technologies that detect and quantify gene mutations.

Liu L, Ma J, Qin L, et al.
Interleukin-24 enhancing antitumor activity of chimeric oncolytic adenovirus for treating acute promyelocytic leukemia cell.
Medicine (Baltimore). 2019; 98(22):e15875 [PubMed] Related Publications
BACKGROUND: Acute promyelocytic leukaemia (APL) is a clonal disease arising by hematopoietic stem cell (HSC), which characterized by inappropriate proliferation/differentiation or survival of immature myeloid progenitors. Oncolytic adenoviruses have been under widespread investigation as anticancer agents. Recently, our data suggested that tumor cells were cured by AdCN205-IL-24, an adenovirus serotype 5-based conditionally replicating adenovirus expressing IL-24 after infection.
METHODS: In this study, we created a novel fiber chimeric oncolytic adenovirus AdCN306-IL-24 that has Ad11 tropism and approved CAR (coxsackie adenovirus receptor, CAR)-independent cell entry, which could allow development of selective cytopathic effects (CPE) in APL cells in vitro.
RESULTS: Formidable cytotoxic effect was specifically implemented in APL cells after infection with AdCN306-IL-24. The expression of IL-24 was up-regulated upon treated with accepted tumors. And the vector also induced superior cytolytic effects activity in APL cells by activation of programmed cell death.
CONCLUSIONS: Taken together, our data suggested that chimeric oncolytic adenovirus AdCN306-IL-24 could express IL-24 gene, representing a potential therapeutics for acute promyelocytic leukemia.

Karantanos T, Jones RJ
Acute Myeloid Leukemia Stem Cell Heterogeneity and Its Clinical Relevance.
Adv Exp Med Biol. 2019; 1139:153-169 [PubMed] Related Publications
The failure of complete remissions to reliably translate into cures in acute myeloid leukemia (AML) can be explained by the leukemia stem cell (LSC) paradigm, which hypothesizes that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, the ability to generate AML in immunocompromised mice were how these so-called LSCs were identified. Only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34

Chen C, Wang P, Wang C
Prognostic nomogram for adult patients with acute myeloid leukemia: A SEER database analysis.
Medicine (Baltimore). 2019; 98(21):e15804 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Acute myeloid leukemia (AML) is hematopoietic malignancy. This study was designed to develop an individualized prognostic nomogram to predict cancer-specific survival (CSS) and overall survival (OS) of AML.The clinical data of AML patients (n = 58,882) diagnosed from 1973 to 2014 were obtained from the Surveillance, Epidemiology, and End Results database. The patients were divided into training cohort (n = 29,441) and validation cohort (n = 29,441). The prognostic nomograms were designed with clinical variables selected by multivariate Cox regression model in training cohort. The concordance index (C-index), calibration curve, and receiver operating characteristic curve were used to assess the performance of the nomograms.The predictors in nomogram for CSS were AML subtypes, age, sex, region, marital status, and chemotherapy, whereas the predictors for OS were AML subtypes, age, sex, region, race, marital status, and chemotherapy. The C-indexes of the nomograms in internal validation for CSS and OS were 0.712 and 0.703, respectively, whereas the C-indexes in external validation for CSS and OS were 0.712 and 0.705, respectively. The area under the curve of receiver operating characteristic curves for CSS and OS were 0.799 (95% confidence interval: 0.792-0.806) and 0.809 (95% confidence interval: 0.803-0.816), respectively.The individualized prognostic nomogram could perform relatively accurate prediction of outcome in adult patients with AML.

Forthun RB, Hellesøy M, Sulen A, et al.
Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.
J Cancer Res Clin Oncol. 2019; 145(7):1729-1749 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
PURPOSE: Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics.
METHODS: The anti-leukemic effects of IFNα and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFNα-2b and human IFNα-Le in MOLM-13 cells by IMAC/2D DIGE/MS analysis and phospho-flow cytometry, and in primary healthy and AML patient-derived PBMCs by CyTOF. In vivo, IFNα-Le and VPA efficacy were investigated in the immunodeficient NOD/Scid IL2γ-/- MOLM-13
RESULTS: IFNα-2b and IFNα-Le differed in the modulation of phospho-proteins involved in protein folding, cell stress, cell death and p-STAT6 Y641, whereas VPA and IFNα-Le shared signaling pathways involving phosphorylation of Akt (T308), ERK1/2 (T202/T204), p38 (T180/Y182), and p53 (S15). Both IFNα compounds induced apoptosis synergistically with VPA in vitro. However, in vivo, VPA monotherapy increased survival, but no benefit was observed by IFNα-Le treatment. CyTOF analysis of primary human PBMCs indicated that lack of immune-cell activation could be a reason for the absence of response to IFNα in the animal models investigated.
CONCLUSIONS: IFNα-2b and IFNα-Le showed potent and synergistic anti-leukemic effects with VPA in vitro but not in leukemic mouse and rat models in vivo. The absence of IFNα immune activation in lymphocyte subsets may potentially explain the limited in vivo anti-leukemic effect of IFNα-monotherapy in AML.

Heng H, Wang Z, Li H, et al.
Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model.
Eur J Med Chem. 2019; 176:248-267 [PubMed] Related Publications
FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.

Drenberg CD, Shelat A, Dang J, et al.
A high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML.
Nat Commun. 2019; 10(1):2189 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

Ossenkoppele G, Montesinos P
Challenges in the diagnosis and treatment of secondary acute myeloid leukemia.
Crit Rev Oncol Hematol. 2019; 138:6-13 [PubMed] Related Publications
Secondary AML (sAML), referring to AML arising after prior cytotoxic/radiation/immunosuppressive therapy (tAML) or an antecedent hematologic disorder, now primarily classified as AML with myelodysplasia-related changes (AML-MRC), accounts for 10%-30% of AML cases and is associated with a poor prognosis. sAML has historically been treated with intensive chemotherapy (eg, 7 + 3) or less aggressive regimens (eg, low-dose cytarabine or azacytidine for older/unfit patients); however, outcomes are typically poor, especially for older adults. Recently, CPX-351, a liposomal co-encapsulation of cytarabine and daunorubicin at a synergistic ratio, demonstrated improved front-line outcomes in older patients with high-risk/sAML. CPX-351 has been approved for adults with newly diagnosed tAML or AML-MRC and has an NCCN category 1 recommendation for induction therapy of patients aged >60 years with high-risk/sAML. Other novel therapies may also benefit certain sAML subgroups. Greater clarity around the optimal diagnosis and treatment of sAML patients is needed to improve outcomes in this high-risk subpopulation.

Masetti R, Guidi V, Ronchini L, et al.
The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children.
Crit Rev Oncol Hematol. 2019; 138:132-138 [PubMed] Related Publications
Pediatric non-Down-syndrome acute megakaryoblastic leukemia (non-DS-AMKL) is a heterogeneous subtype of leukemia that has historically been associated with poor prognosis. Until the advent of large-scale genomic sequencing, the management of patients with non-DS-AMKL was very difficult due to the absence of reliable biological prognostic markers. The sequencing of large cohort of pediatric non-DS-AMKL samples led to the discovery of novel genetic aberrations, including high-frequency fusions, such as CBFA2T3-GLIS2 and NUP98-KDM5 A, as well as less frequent aberrations, such as HOX rearrangements. These new insights into the genetic landscape of pediatric non-DS-AMKL has allowed refining the risk-group stratification, leading to important changes in the prognostic scenario of these patients. This review summarizes the most important molecular pathogenic mechanisms of pediatric non-DS-AMKL. A critical discussion on how novel genetic abnormalities have refined the risk profile assessment and changed the management of these patients in clinical practice is also provided.

Wang X, Wang J, Zhang L
Characterization of atypical acute promyelocytic leukaemia: Three cases report and literature review.
Medicine (Baltimore). 2019; 98(19):e15537 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
RATIONALE: The vast majority of acute promyelocytic leukemia (APL) is characterized with a specific chromosomal translocation t (15, 17) (q22, q21), which fuses PML-RARα leading to a good response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, there are few cases of atypical APL, including PLZF-RARα, F1P1L1-RARα, STAT5b-RARα, et al. Neither PLZF-RARα nor STAT5b-RARα are sensitive to ATRA and ATO, and the prognosis is poor.
PATIENT CONCERNS: Here we have 3 cases (PLZF-RARα, n = 2; STAT5b-RARα, n = 1). Case A, A 53-year-old Chinese female had suffered ecchymosis in both legs for 3 days. Case B, A 44 years old male suffered pain from lower limbs and hip. Case C, 52-year-old male patient presented with fever for 3 weeks invalid to antibiotics and gingival bleeding for 1 week.
DIAGNOSES: With RT-PCR and karyotype, Case A is diagnosed with STAT5b-RARα-positive APL.Case B, C are diagnosed with PLZF-RARα-positive APL.
INTERVENTIONS: In case A, ATO, and ATRA were used for induction treatment. In Case B, ATO, and chemotherapy with DA were given in the first induction treatment. In Case C, ATRA, and ATO were used immediately, subsequently, chemotherapy was added with DA, ATRA, and CAG combination treatment, and medium-dose cytarabine with daunorubicin were given regularly.
OUTCOMES: In Case A, the patient refused the following treatment and discharged on day 25. In Case B, the patient got the disseminated intravascular coagulation (DIC).In Case C, the patient has survived for 7 months and remains CR.
LESSONS: Both STAT5b-RARα-positive APL and PLZF-RARα-positive APL appear to be resistant to both ATRA and ATO, so combined chemotherapy and allo-HSCT should be considered. Since the prognosis and long-term outcome are poor, more clinical trials, and researches should be taken.

Hu J, Sun Q, Fang W, Wang Q
Effect of combination of all-trans retinoic acid and arsenic trioxide on apoptosis of acute promyelocytic leukemia cells.
Cell Mol Biol (Noisy-le-grand). 2019; 65(4):97-100 [PubMed] Related Publications
To study the effect of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination treatment on apoptosis of acute promyelocytic leukemia cells (NB4), inflammation and prognosis. The effect of ATRA - ATO combination on the proliferation of NB4 was determined using MTT assay. Apoptosis of NB4 cells was assessed with TUNEL assay. The effect of ATRA-As2O3 combination on the expressions of IL-6 and TNF-α in NB4 cells was determined using ELISA kits, while its effect on the quality of life of 25 acute promyelocytic leukemia patients admitted to our hospital was scored, as an index of prognosis. The combination treatment with ATRA and ATO significantly inhibited the proliferation of NB4 cells and promoted their apoptosis, relative to the model group. In addition, the combination treatment reduced serum IL-6 and TNF-α levels in patients with acute promyelocytic leukemia, and improve their quality of life and survival. Combination treatment with ATRA and ATO significantly inhibits the proliferation of NB4 cells and promotes their apoptosis, and reduces inflammatory responses in patients with acute promyelocytic leukemia, while improving their quality of life and prognosis.

Heo SK, Noh EK, Jeong YK, et al.
Radotinib inhibits mitosis entry in acute myeloid leukemia cells via suppression of Aurora kinase A expression.
Tumour Biol. 2019; 41(5):1010428319848612 [PubMed] Related Publications
Aurora kinases play critical roles in regulating several processes pivotal for mitosis. Radotinib, which is approved in South Korea as a second-line treatment for chronic myeloid leukemia, inhibits the tyrosine kinase BCR-ABL and platelet-derived growth factor receptor. However, the effects of radotinib on Aurora kinase expression in acute myeloid leukemia are not well studied. Interestingly, the cytotoxicity of acute myeloid leukemia cells was increased by radotinib treatment. Radotinib significantly decreased the expression of cyclin-dependent kinase 1 and cyclin B1, the key regulators of G2/M phase, and inhibited the expression of Aurora kinase A and Aurora kinase B in acute myeloid leukemia cells. In addition, radotinib decreased the expression and binding between p-Aurora kinase A and TPX2, which are required for spindle assembly. Furthermore, it reduced Aurora kinase A and polo-like kinase 1 phosphorylation and suppressed the expression of α-, β-, and γ-tubulin in acute myeloid leukemia cells. Furthermore, radotinib significantly suppressed the key regulators of G2/M phase including cyclin B1 and Aurora kinase A in a xenograft animal model. Therefore, our results suggest that radotinib can abrogate acute myeloid leukemia cell growth both in vitro and in vivo and may serve as a candidate agent or a chemosensitizer for treating acute myeloid leukemia.

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