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Translational Pediatrics Feb 2024
PubMed: 38455741
DOI: 10.21037/tp-23-536 -
Panminerva Medica Feb 2024
PubMed: 38411405
DOI: 10.23736/S0031-0808.24.05064-X -
Blood Cancer Journal Feb 2024Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors...
Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
Topics: Humans; Animals; Mice; Core Binding Factor Alpha 2 Subunit; Leukemia, Myeloid, Acute; Homoharringtonine; Blood Platelets; Blood Platelet Disorders; Proto-Oncogene Proteins c-bcl-2
PubMed: 38316746
DOI: 10.1038/s41408-024-00981-4 -
Medicine Jan 2024With the advancement of diagnostic technology, true acute undifferentiated leukemia (AUL) is becoming more rare, and AUL with extramedullary sarcoma has not been... (Review)
Review
BACKGROUND
With the advancement of diagnostic technology, true acute undifferentiated leukemia (AUL) is becoming more rare, and AUL with extramedullary sarcoma has not been reported.
CASE PRESENTATION
This article reports a case of AUL with extramedullary sarcoma. Flow cytometric analysis of the bone marrow and lymph nodes indicated that the tumor cells of both were of the same origin and mainly expressed stem cell markers and CD7, no myeloid-specific markers, T-lymphoblastic-related markers, and B-lymphoblastic-related markers. Although the priming regimen combined with azacitidine was ineffective, complete remission was achieved by switching to azacitidine combined with HIA (homoharringtonine, idarubicin plus Ara-C).
CONCLUSION
To diagnosis de novo acute leukemia with extensive and comprehensive cellular immune maker detection is available and credible, the expression of a single relatively nonspecific myeloid antigen as a immune maker to detect AUL or AUL associated with sarcoma is precise and effective in our case, which patient was benefit from HIA regiment.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Bone Marrow; Acute Disease; Azacitidine
PubMed: 38277531
DOI: 10.1097/MD.0000000000036948 -
Frontiers in Oncology 2023SSBP2-CSF1R is an important biomarker for clinical diagnosis and prognosis of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). This case report...
SSBP2-CSF1R is an important biomarker for clinical diagnosis and prognosis of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). This case report presents a pediatric Ph-like ALL patient carrying the SSBP2-CSF1R fusion gene. The patient was resistant to most conventional chemotherapy regimens and to dasatinib, an inhibitor that has been reported to have a therapeutic effect on SSBP2-CSF1R fusion Ph-like ALL, as she remained minimal residual disease (MRD) positive (detection by flow cytometry) and SSBP2-CSF1R fusion gene (detection by RT-PCR) positive after five rounds of such regimens. We thus conducted a large-scale screening to assess the sensitivity of the patient's leukemic cells to anti-cancer drugs. Based on the susceptibility results, we chose to combine cytarabine, homoharringtonine, dexamethasone, fludarabine, vindesine, and epirubicin for treatment. Clinical results showed that after a course of treatment, both MRD and SSBP2-CSF1R fusion gene turned negative, and there was no recurrence during an 18-month follow-up. In conclusion, our study suggests that the SSBP2-CSF1R fusion gene may be an important biomarker of primary drug resistance in Ph-like ALL, and indicate that the combination of cytarabine, homoharringtonine, dexamethasone, fludarabine, vindesine, and epirubicin can achieve optimal therapeutic results in this category of patients.
PubMed: 38107066
DOI: 10.3389/fonc.2023.1291570 -
European Review For Medical and... Dec 2023Explore the efficacy of decitabine combined with homoharringtonine + cytarabine + granulocyte colony-stimulating factor (HAG) in the treatment of acute myeloid leukemia...
OBJECTIVE
Explore the efficacy of decitabine combined with homoharringtonine + cytarabine + granulocyte colony-stimulating factor (HAG) in the treatment of acute myeloid leukemia (AML).
PATIENTS AND METHODS
A retrospective analysis of clinical data of 125 patients with AML was done. Of them, 61 patients received a simple HAG treatment (HAG group), and 64 received decitabine combined with an HAG regimen (combined group). Treatment efficacy, immune function before and after the treatment, levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and incidence of adverse reactions in the two groups were compared.
RESULTS
The total response rate of the combined group (84.38%) was higher than that of the HAG group (65.63%) (p < 0.05). After the treatment, levels of CD4+ and CD4+/CD8+ in both groups increased and were significantly higher in the combined group compared to the HAG group. Levels of CD8+, bFGF and VEGF decreased compared to pre-treatment levels and were significantly lower in the combined group than in the HAG group (p < 0.05). There was no significant difference in the rate of adverse reactions between the two groups (p > 0.05).
CONCLUSIONS
Compared to HAG treatment alone, the combination of decitabine and HAG in the treatment of AML is safe, can significantly improve the immune function of the patients, regulate bFGF and VEGF levels, and improve overall treatment efficacy.
Topics: Humans; Decitabine; Vascular Endothelial Growth Factor A; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Treatment Outcome; Leukemia, Myeloid, Acute; Fibroblast Growth Factor 2
PubMed: 38095382
DOI: 10.26355/eurrev_202312_34572 -
EJHaem Nov 2023Adverse-risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine...
Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis.
Adverse-risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse-risk AML. Thirteen de novo AML patients with adverse-risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3-21), HHT (1 mg/m days 1-5) and cytarabine (100 mg/m days 1-5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi-parameter flow cytometry (MFC). Grade 3-4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3-4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow-up of 10 months (range 4-19), median overall survival and event-free survival were not reached. VHA may be a promising and well-tolerated regimen in de novo adverse-risk AML.
PubMed: 38024627
DOI: 10.1002/jha2.792 -
Chinese Medical Journal Jun 2024Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the...
BACKGROUND
Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.
METHODS
Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation.
RESULTS
HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo . Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4 , H2-Eb1 , TRAT1 , and CD74 ) and upregulated the expression of IL-10 and transforming growth factor (TGF)-β pathway-related genes and Treg signature genes ( CTLA4 , Foxp3 , CD74 , and ICOS ). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo , and it enhanced the inhibitory function of inducible Tregs.
CONCLUSIONS
HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.
Topics: Animals; T-Lymphocytes, Regulatory; Heart Transplantation; Mice; Mice, Inbred C57BL; Homoharringtonine; Graft Survival; Male; Allografts; Harringtonines; Mice, Inbred BALB C
PubMed: 37962205
DOI: 10.1097/CM9.0000000000002813 -
Journal of Biological Rhythms Feb 2024Circadian-paced biological processes are key to physiology and required for metabolic, immunologic, and cardiovascular homeostasis. Core circadian clock components are...
Circadian-paced biological processes are key to physiology and required for metabolic, immunologic, and cardiovascular homeostasis. Core circadian clock components are transcription factors whose half-life is precisely regulated, thereby controlling the intrinsic cellular circadian clock. Genetic disruption of molecular clock components generally leads to marked pathological events phenotypically affecting behavior and multiple aspects of physiology. Using a transcriptional signature similarity approach, we identified anti-cancer protein synthesis inhibitors as potent modulators of the cardiomyocyte molecular clock. Eukaryotic protein translation inhibitors, ranging from translation initiation (rocaglates, 4-EGI1, etc.) to ribosomal elongation inhibitors (homoharringtonine, puromycin, etc.), were found to potently ablate protein abundance of REV-ERBα, a repressive nuclear receptor and component of the molecular clock. These inhibitory effects were observed both in vitro and in vivo and could be extended to PER2, another component of the molecular clock. Taken together, our observations suggest that the activity spectrum of protein synthesis inhibitors, whose clinical use is contemplated not only in cancers but also in viral infections, must be extended to circadian rhythm disruption, with potential beneficial or iatrogenic effects upon acute or prolonged administration.
Topics: Circadian Clocks; Circadian Rhythm; Protein Synthesis Inhibitors; Nuclear Receptor Subfamily 1, Group D, Member 1; Heart
PubMed: 37872767
DOI: 10.1177/07487304231202561 -
Biochimica Et Biophysica Acta.... Jan 2024Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding...
BACKGROUND
Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding motif protein 39 (RBM39) in AML cell proliferation, apoptosis, and chemosensitivity, and its potential modulation of the PI3K/AKT pathway.
METHODS
In vitro and in vivo experiments were conducted using AML cell lines (K562 and U937) and bone marrow mononuclear cells (BM-MNCs) from AML patients and healthy donors. RBM39 mRNA and protein levels were measured using qRT-PCR and Western blotting. Cells were transfected with sh-RBM39 or sh-control, and then treated with daunorubicin (DNR) or homoharringtonine (HHT) at varied concentrations. Cell proliferation, chemosensitivity, and apoptosis were assessed through CCK-8 assay and Annexin V-APC/PI staining. RNA sequencing identified differentially expressed genes (DEGs) post RBM39 knockdown. An in vivo xenograft AML model using E7070, a selective RBM39 inhibitor, was employed to evaluate RBM39 modulation effects.
RESULTS
Elevated RBM39 levels were found in AML patients and cell lines compared to controls. RBM39 knockdown promoted apoptosis, curtailed cell proliferation, and enhanced chemosensitivity to DNR and HHT in vitro. Drug-resistant or relapsed AML patients displayed higher RBM39 levels. RNA sequencing after RBM39 knockdown revealed downregulated PI3K/AKT signaling. The xenograft model validated in vitro results, as E7070 treatment suppressed AML xenograft growth via RBM39-mediated PI3K/AKT pathway suppression.
CONCLUSION
RBM39 plays a pivotal role in AML progression through the PI3K/AKT signaling pathway. Targeting RBM39, potentially with E7070, could inhibit proliferation and induce apoptosis in AML cells, offering a promising avenue for future AML research and treatment.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Leukemia, Myeloid, Acute; Daunorubicin
PubMed: 37852323
DOI: 10.1016/j.bbamcr.2023.119607