^
1d
Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy. (PubMed, Cancers (Basel))
More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities.
Review • Journal
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PML (Promyelocytic Leukemia)
|
arsenic trioxide
7d
A Case of Relapsed/Refractory CD56-Positive Acute Promyelocytic Leukemia, in Which Complete Molecular Remission Was Achieved Following Combination Therapy with Venetoclax and Azacitidine. (PubMed, Gan To Kagaku Ryoho)
In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.
Journal • Combination therapy
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RARA (Retinoic Acid Receptor Alpha) • NCAM1 (Neural cell adhesion molecule 1)
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NCAM1 positive
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Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
9d
The CDK4/6 inhibitor Palbociclib synergizes with ATRA to induce differentiation in AML. (PubMed, Mol Cancer Ther)
These enhanced differentiation effects may be associated with the regulation of transcription factors, including RARα, E2F1, and STAT1. Overall, our findings demonstrate that CDK4/6 inhibition sensitizes AML cells to ATRA and could guide the development of novel therapeutic strategies for AML patients.
Journal
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RARA (Retinoic Acid Receptor Alpha) • STAT1 (Signal Transducer And Activator Of Transcription 1) • E2F1 (E2F transcription factor 1)
|
Ibrance (palbociclib)
17d
USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression. (PubMed, Cell Death Discov)
Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.
Journal
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RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • USP22 (Ubiquitin Specific Peptidase 22)
22d
Clinical analysis of 82 cases of acute promyelocytic leukemia with PML-RARα short isoform in children and adults. (PubMed, Front Oncol)
The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (P=0.019 and P=0.017, respectively). ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with PML-RARα short isoform.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • BCR (BCR Activator Of RhoGEF And GTPase) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
27d
MANIFEST: A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis (clinicaltrials.gov)
P1/2, N=336, Active, not recruiting, Constellation Pharmaceuticals | Trial primary completion date: Dec 2023 --> Oct 2024
Trial primary completion date
|
Jakafi (ruxolitinib) • hydroxyurea • pelabresib (CPI-0610)
27d
Veliparib and Temozolomide in Treating Patients With Acute Leukemia (clinicaltrials.gov)
P1, N=66, Active, not recruiting, National Cancer Institute (NCI)
Trial completion date • Combination therapy
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Chr t(15;17)
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temozolomide • veliparib (ABT-888)
1m
Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia. (PubMed, Int J Hematol)
The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved...However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
arsenic trioxide
1m
Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia. (PubMed, Nat Commun)
Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
|
FLT3-ITD mutation
1m
Trial completion
|
HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
|
Promune (agatolimod)
2ms
High-Fat Diet Induced PPARδ Promotes Self-renewal of Preleukemic Progenitors in Development of Acute Promyelocytic Leukemia. (PubMed, Cancer Prev Res (Phila))
Involvements of PPARδ on regulation of stem cell renewal and proliferation were shown in colorectal cancers earlier, but this study newly demonstrates in hematopoietic progenitors, while suggesting use of diet rich in linoleic acid with caution. See related article by Mazzarella et al., p. 59.
Journal
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RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
2ms
Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway. (PubMed, J Ethnopharmacol)
We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PML-RARα.
Journal
|
RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
2ms
Acute promyelocytic leukemia with PML/RARA (bcr1, bcr2 and bcr3) transcripts in a pediatric patient. (PubMed, Oncol Lett)
However, the results of the present study confirmed that they may also be present in APL. Thus, these findings suggested a possible signaling pathway that involves the PML/RARA oncoprotein in APL.
Journal
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BCR (BCR Activator Of RhoGEF And GTPase)
|
Chr t(15;17) • Chr t(15;17)/PML-RARA fusion
2ms
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion. (PubMed, Nat Commun)
CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.
Journal • Cancer stem
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IGF1 (Insulin-like growth factor 1) • CFLAR (CASP8 and FADD-like apoptosis regulator)
2ms
Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia. (PubMed, Ann Hematol)
Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.
Journal
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RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
|
Chr t(15;17)
2ms
Parbendazole as a promising drug for inducing differentiation of acute myeloid leukemia cells with various subtypes. (PubMed, Commun Biol)
Finally, an in vivo analysis using an AML patient-derived xenograft mouse model showed a significant decrease in the chimerism level and prolonged survival in PBZ-treated mice. These findings could lead to a more effective differentiation therapy for AML.
Journal
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KLF4 (Kruppel-like factor 4) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • DPYSL2 (Dihydropyrimidinase Like 2)
2ms
Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors. (PubMed, Curr Issues Mol Biol)
Finally, we found that ATO inhibited the expression of the important endothelial cell receptors VEGFR-2, VEGFR-3, Tie-2 and Lyve-1. In conclusion, we demonstrate that ATO inhibits lymphangiogenesis by activating apoptotic pathways and inhibiting important endothelial cell receptors, which suggests that this drug should be further evaluated in the treatment of tumor-associated lymphangiogenesis.
Journal
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KDR (Kinase insert domain receptor) • BIRC5 (Baculoviral IAP repeat containing 5) • FLT4 (Fms-related tyrosine kinase 4) • CASP8 (Caspase 8) • CASP9 (Caspase 9) • XIAP (X-Linked Inhibitor Of Apoptosis) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • LYVE1 (Lymphatic vessel endothelial hyaluronan receptor 1)
|
arsenic trioxide
2ms
Analysis of the clinical characteristics of acute myeloid leukemia related to the treatment of hematological and solid tumors (PubMed, Zhonghua Zhong Liu Za Zhi)
Compared with patients with t-AML secondary to solid tumors, patients with t-AML secondary to hematological tumors have poorer treatment effects and poorer prognosis. After excluding the effect of t-APL patients, there are no significant differences in the treatment efficacy and prognosis between the two types of t-AML patients.
Journal
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PML (Promyelocytic Leukemia)
2ms
Journal
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WT1 (WT1 Transcription Factor) • GATA2 (GATA Binding Protein 2)
|
WT1 mutation
2ms
New Chalcone Derivatives Containing 2,4-Dichlorobenzenesulfonamide Moiety with Anticancer and Antioxidant Properties. (PubMed, Int J Mol Sci)
To determine the antibacterial activity of derivatives 4-8, the minimum bacteriostatic concentration (MIC) values were estimated (>500 µg/mL for all the tested bacterial strains). The findings demonstrate the substantial potential of sulfonamide-based chalcone 5 as a promising drug in anticancer therapy.
Journal
|
CASP8 (Caspase 8) • CASP9 (Caspase 9)
3ms
Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS. (PubMed, Anticancer Agents Med Chem)
EA+ATRA induced cell apoptosis through ROS dependent MMP attenuation and caspase 3/7 activation while inducing differentiation by ROS-MEK/ERK-PU.1/C/EBPs and ROS-Akt-PU.1/C/EBPs pathways. In summary, it may provide innovative ATRA-based combination therapy strategies for AML patients via ROS.
Journal
|
CASP3 (Caspase 3) • CASP7 (Caspase 7) • ITGAX (Integrin Subunit Alpha X) • ANXA5 (Annexin A5)
3ms
Harnessing intermolecular G-quadruplex-based spatial confinement effect for accelerated activation of CRISPR/Cas12a empowers ultra-sensitive detection of PML/RARA fusion genes. (PubMed, Anal Chim Acta)
The robust detection of PML/RARA fusion gene from human serum samples validates the reliability and potential of this platform in the screening, diagnosis, and prognosis of APL cases. Our findings present an approach that holds significant potential for the further development of the robust CRISPR/Cas sensor system, offering a rapid and adaptable paradigm for APL diagnosis.
Journal
|
PML (Promyelocytic Leukemia)
|
PML-RARA fusion
3ms
Identification of concurrent STAT3::RARA and RARA::STAT5b fusions in a variant APL case. (PubMed, Mol Carcinog)
Then, this patient was resistant to all-trans retinoic acid combined arsenic trioxide chemotherapy. Accurate detection of RARA gene partners is crucial for variant APL, and effective therapeutic regime is urgently needed.
Journal
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STAT3 (Signal Transducer And Activator Of Transcription 3) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
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arsenic trioxide
3ms
Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia. (PubMed, Front Med)
The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research...Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.
Journal
|
IFNG (Interferon, gamma)
|
arsenic trioxide
3ms
Mutations at proximal cysteine residues in PML impair ATO binding by destabilizing the RBCC domain. (PubMed, FEBS J)
Acute promyelocytic leukemia (APL) is characterized by the fusion gene promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) and is conventionally treated with arsenic trioxide (ATO)...In addition, these mutations disrupt several hydrogen bonds, including interactions involving C212, C213 and C215, which are essential for ATO binding. The local and global structural features induced by these mutations provide mechanistic insight into ATO resistance and APL pathogenesis.
Journal
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RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
|
PML-RARA A216V • PML-RARA L218P
|
arsenic trioxide
3ms
Effective treatment with Gilteritinib-based regimens for FLT3-mutant extramedullary relapse in acute promyelocytic leukemia. (PubMed, Hematology)
They all maintained molecular complete remission (mCR) during the follow-up period. The Gilteritinib-based regimen shows a high and sustained therapeutic effect with minimal adverse effects, and provides a valuable experience for further evaluation in EMR APL patients.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Xospata (gilteritinib)
4ms
Different Isoforms of PML-RARA Chimeric Protein in Patients with Acute Promyelocytic Leukemia: Survival Analysis per Demographic Characteristics, Clinicohematological Parameters, and Cytogenetic Findings. (PubMed, Iran J Pathol)
In Iranian APL patients, bcr1 predominates, while bcr3 correlates with higher WBC counts, high-risk categorization, additional chromosomal abnormalities, and faster CHR. Survival is negatively impacted by old age, relapse, lower PLT counts, higher WBC counts, and leukocytosis.
Journal
|
BCR (BCR Activator Of RhoGEF And GTPase) • PML (Promyelocytic Leukemia)
|
PML-RARA fusion • Chr t(15;17) • Chr t(15;17)/PML-RARA fusion
4ms
Leukemia cells accumulate zinc for oncofusion protein stabilization. (PubMed, J Nutr Biochem)
Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.
Journal
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CASP3 (Caspase 3)
|
BCR-ABL1 fusion
4ms
Mechanistic update of Trisenox in blood cancer. (PubMed, Curr Res Pharmacol Drug Discov)
We have also provided important information of combination therapy of TX with other molecules mechanism of action in acute leukemia cells. It provides updated information of TX action for researcher which may help finding new target for further research in APL pathophysiology or new TX resistant APL patients drug designing.
Review • Journal
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RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
4ms
AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity. (PubMed, J Med Chem)
Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia...In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.
Journal
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TP53 (Tumor protein P53) • RARA (Retinoic Acid Receptor Alpha)
|
TP53 mutation
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arsenic trioxide
4ms
Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies. (PubMed, Genome Biol)
We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.
Journal
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ATRX (ATRX Chromatin Remodeler) • DAXX (Death-domain associated protein)
|
IDH1 mutation • H3.3K27M
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arsenic trioxide
4ms
Ultrasensitive detection of genetic variation based on dual signal amplification assisted by isothermal amplification and cobalt oxyhydroxide nanosheets/quantum dots. (PubMed, Mikrochim Acta)
Owing to the specific recognition and efficient amplification of tri-HT SDA as well as impressive anti-interference and considerable amplification of CoOOH/QD, this biosensor demonstrated a wide dynamic range (10 fM to 10 nM) with a low limit of detection (5.50 fM) in P/R detection. Additionally, this biosensor could detect P/R spiked into human serum with good recoveries and relative standard deviation (RSD), thus potentially exhibiting ultrasensitive and specific nuclear acid sequence detection ability in clinical diagnosis owing to combing isothermal amplification and nanomaterials.
Journal
|
RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
4ms
A prospective multicenter clinical study of relapsed acute promyelocytic leukemia in children (SCCCG R-APL 2023 protocol) (ChiCTR2300074053)
P=N/A, N=20, Recruiting, The First Affiliated Hospital of Sun Yat-sen University; The First Affiliated Hospital of Sun Yat-sen University
New trial
|
PML (Promyelocytic Leukemia)
|
Chr t(15;17)
4ms
Treatment Outcomes of Stem Cell Transplant in Patients with Acute Myeloid Leukemia Treated with Venetoclax in Combination with Hypomethylating Agents: Experience from Routine Clinical Practices in the United States (ASH 2023)
In this study, similar to findings from clinical trials, we observed a subset of pts with ND AML treated with Ven+HMAs underwent SCT post-remission in routine clinical setting. Compared with pts who did not undergo SCT post-remission, pts who underwent SCT post-remission were younger, and more of these pts received care in academic centers. Of the Ven+HMAs-treated pts who underwent SCT post-remission, more pts treated in the routine clinical setting had the poor prognostic TP53 mutation than pts enrolled in the aforementioned clinical trials.
Clinical • Combination therapy
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
|
TP53 mutation • FLT3 mutation
|
Venclexta (venetoclax)
4ms
Disparities in Genetic Profiles, Risk Stratification and Outcomes in Adults with Acute Myeloid Leukemia Comparing Patients of Hispanic and Non-Hispanic Ethnicity in Central California (ASH 2023)
Our study identified biologic differences between Hispanic and non-Hispanic AML patients with heterogeneity in genetic mutations. While Hispanic patients had lower income, they were younger at diagnosis and more likely to have favorable risk AML. Hispanic patients had better PFS and a trend towards improvement in OS.
Clinical
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2C (Lysine Methyltransferase 2C) • STAG2 (Stromal Antigen 2)
|
TP53 mutation • FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation
|
FoundationOne® Heme CDx
4ms
Transfer of mRNA Encoding CEBPA in Lipid Nanoparticles to CEBPA Mutated Leukemia Cell Line KO52 and Primary AML Reduces Cell Growth and Induces Myeloid Differentiation (ASH 2023)
Our findings reveal a novel therapeutic strategy using CEBPA mRNA LNP applicable to inherited or acquired disorders of CEBPA. This approach of restoration of normal mRNA could have potential for therapy of many pre-malignant and malignant disorders.
Preclinical • IO biomarker
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • CD34 (CD34 molecule) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • ANPEP (Alanyl Aminopeptidase, Membrane) • ANXA5 (Annexin A5)
|
CEBPA mutation
4ms
Use of CLL1 and CD45RA As Biomarkers for Leukemia Stem Cells in Acute Myeloid Leukemia Re-Induction Therapy Decision Making (ASH 2023)
In newly diagnosed AML with high percent of CLL1 +/CD34 +CD38 - or CD45RA +/CD34 +CD38 - LSC subset on diagnosis, monitoring LSC subset offers additional information regarding efficacy of induction therapy. All the patients with CR showed residual LSC subset of 0. 5-fold or less compared to LSC subset on diagnosis (defined as “adequate reduction” of LSC subset).
IO biomarker
|
CD38 (CD38 Molecule) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C)
4ms
Podoplanin Expression Measured By Flow Cytometry Accurately Identifies Patients with Acute Promyelocytic Leukemia at Diagnosis (ASH 2023)
In conclusion, our prospective study demonstrated that measurement of the expression of PDPN by flow cytometry at diagnosis is capable to accurately segregate APL from other forms of AML. Additional studies are warranted to explore the clinical association of PDPN expression in larger and independent cohorts.
Clinical
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD33 (CD33 Molecule) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • ANPEP (Alanyl Aminopeptidase, Membrane)
4ms
Research on Different Compound Combinations of Realgar-Indigo Naturalis Formula to Reverse APL Arsenic Resistance By Regulating Autophagy through mTOR Pathway (ASH 2023)
All-trans retinoic acid and arsenic trioxide is able to cure 90% of APL patients by targeting PML-RARα...The PI3K inhibitor LY294002 and the autophagy inhibitor Baf A1 were combined and applied to observe the changes in the levels of PML A216V-RARα, mTOR and p62 after blocking the PI3K or autophagy pathway... The arsenic-resistant cell line HL60-PML A216V-RARα was successfully established. Compared with the control group, A, ITS and AITS groups all inhibited the growth of HL60-PML A216V-RARα cells in a time-dependent manner ( P < 0. 0001).
PARP Biomarker • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • RARA (Retinoic Acid Receptor Alpha) • CD33 (CD33 Molecule) • PML (Promyelocytic Leukemia) • CASP3 (Caspase 3) • ANXA5 (Annexin A5)
|
CD33 expression
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LY294002 • arsenic trioxide