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Project description:Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia development is obscure. Here, we conducted a retrospective study containing 1,412 medical records (319 APL, 393 non-APL acute myeloid leukemia (AML), and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non-APL AML and non-tumor controls. We revealed that triglyceride served as a risk factor of early death in APL patients, and there was a positive correlation between high triglyceride levels and high leukocyte counts. RNA-seq analysis on APL patients with high or normal triglyceride levels brought attention to peroxisome proliferator-activated receptor-alpha (PPARα) signaling, a crucial regulator of cell metabolism and a transcription factor involved in cancer development. We demonstrated that PPARα knockdown inhibited the proliferation of APL cells. Chromatin mapping data analysis with CUT&Tag revealed that PPARα coexisted with PML/RARα within the super-enhancer regions to maintain APL. Interventions to PPARα affected the transcription and protein level of FLT3. Moreover, in vivo results in mice having high-fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemia burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL cell proliferation and high triglyceride levels and established the contribution of an hyperlipidemia–PPARα–FLT3 axis to APL development.
2022-11-02 | GSE195777 | GEO
Project description:Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia development is obscure. Here, we conducted a retrospective study containing 1,412 medical records (319 APL, 393 non-APL acute myeloid leukemia (AML), and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non-APL AML and non-tumor controls. We revealed that triglyceride served as a risk factor of early death in APL patients, and there was a positive correlation between high triglyceride levels and high leukocyte counts. RNA-seq analysis on APL patients with high or normal triglyceride levels brought attention to peroxisome proliferator-activated receptor-alpha (PPARα) signaling, a crucial regulator of cell metabolism and a transcription factor involved in cancer development. We demonstrated that PPARα knockdown inhibited the proliferation of APL cells. Chromatin mapping data analysis with CUT&Tag revealed that PPARα coexisted with PML/RARα within the super-enhancer regions to maintain APL. Interventions to PPARα affected the transcription and protein level of FLT3. Moreover, in vivo results in mice having high-fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemia burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL cell proliferation and high triglyceride levels and established the contribution of an hyperlipidemia–PPARα–FLT3 axis to APL development.
2022-11-02 | GSE195776 | GEO
Project description:A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα.
| PRJNA802131 | ENA
Project description:A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα. [CUT&Tag]
| PRJNA802139 | ENA
Project description:A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα. [RNA-Seq]
| PRJNA802138 | ENA
Project description:Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-α (PML/RARα), generated by the chromosome translocation t(15;17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here, we provide rich evidence of how PML/RARα drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RARα is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, 2 widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RARα-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RARα, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RARα on chromatin in coregulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.
| S-EPMC7976511 | biostudies-literature
Project description:BackgroundThe confirmation of clinical diagnosis, molecular remission, and sequential minimal residual disease monitoring required PML-RARα detection in acute promyelocytic leukemia (APL). The current status of PML-RARα detection in various laboratories remains unknown.MethodsIn 2018, external quality assessment (EQA) for PML-RARα detection was carried out in China. Three EQA sample panels for PML-RARα isoform L/S/V were prepared by different mock leukocyte samples. The performances of PML-RARα detection, including admission screening, and qualitative and quantitative detection by real-time quantitative reverse transcription PCR (RT-qPCR), were assessed based on APL simulated clinical case.ResultsThe mock leukocyte samples met the requirements of a clinically qualified sample for PML-RARα EQA panel. Among the laboratories, 13/50 (26.0%) were "competent," 21/50 (42%) classified as "acceptable," and 16/50 (32.0%) classified as "improvable." One (1/50, 2.0%) laboratory reported one screening mistake. Twenty-six (26/50, 52.0%) laboratories reported 29 false-positive and 19 false-negative results. Twenty-three (23/50, 46.0%) laboratories reported 42 quantitative incorrect results.ConclusionSignificant differences were not found in PML-RARα detection performance among laboratories that used different extraction methods. The performances of qualitative and quantitative RT-qPCR detection were worse accurate for PML-RARα isoform V. Quantitative variation was higher for low-level samples. Further continuous external assessment and education are needed in the management of PML-RARα detection.
| S-EPMC6642306 | biostudies-literature
Project description:Acute promyelocytic leukemia (APL) is epitomized by the chromosomal translocation t(15;17) and the resulting oncogenic fusion protein PML-RARα. Although acting primarily as a transcriptional repressor, PML-RARα can also exert functions of transcriptional co-activation. Here, we find that PML-RARα stimulates transcription driven by HIF factors, which are critical regulators of adaptive responses to hypoxia and stem cell maintenance. Consistently, HIF-related gene signatures are upregulated in leukemic promyelocytes from APL patients compared to normal promyelocytes. Through in vitro and in vivo studies, we find that PML-RARα exploits a number of HIF-1α-regulated pro-leukemogenic functions that include cell migration, bone marrow (BM) neo-angiogenesis and self-renewal of APL blasts. Furthermore, HIF-1α levels increase upon treatment of APL cells with all-trans retinoic acid (ATRA). As a consequence, inhibiting HIF-1α in APL mouse models delays leukemia progression and exquisitely synergizes with ATRA to eliminate leukemia-initiating cells (LICs).
| S-EPMC4023886 | biostudies-literature
Project description:PHRF1 functions as an essential component of the TGF-β tumor suppressor pathway by triggering degradation of the homeodomain repressor factor TGIF. This leads to redistribution of cPML into the cytoplasm, where it coordinates phosphorylation and activation of Smad2 by the TGF-β receptor. In acute promyelocytic leukemia (APL), acquisition of PML-RARα is known to impede critical aspects of TGF-β signaling, including myeloid differentiation. Although these defects are thought to rely on suppression of cPML activity, the mechanisms underlying this phenomenon remain enigmatic. Here, we find that an abnormal function of PML-RARα is to interfere with TGIF breakdown, presumably by competing with PHRF1 for binding to TGIF, culminating in cPML sequestration and inactivation. Enforcing PHRF1 activity is sufficient to restore TGF-β cytostatic signaling in human blasts and suppress APL formation in a mouse model of APL, providing proof-of-concept data that suppression of PHRF1 activity by PML-RARα represents a critical determinant in APL pathogenesis.
| S-EPMC4532664 | biostudies-literature
Project description:Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.
| S-EPMC7481410 | biostudies-literature