Overview
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Key numbers
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- based therapies render APL the most curable subtype of AML, yet approximately 1% of cases are resistant and 5% relapse. We
- alters DNA repair and oxidoreductive state of the cell, promotes Approximately 1% of APL cases are resistant to ATRA/ATO therapy
- self-renewal of APL initiating cells and leukemia progression (5–8). and 5% APL cases relapse, eventually becoming resistant to treatment
- sudden onset, make for a complex biological background yet to ATRA and ATO binding domains are found in 27 to 45% of resistant
- production, were measured in primary blasts from APL patients (n = 7), hematopoietic precursors /progenitors (EP/P) at day 7 (N7, mostly
- promyelocytes, n = 3), and day 13 (N13 mostly neutrophil granulocytes, n = 3), and in normal bone marrow (NBM, n = 2). Molecular and
- clinical characterization of APL primary blast is shown in Supplementary Table-S1 (N°1 to 7). Statistical analysis was performed using the non-
- transcriptional profile analysis and metabolic characterization of Germany) (27). The primer sequences are listed in Supplementary Table S5.
- for disease evolution, response and resistance to therapy (24). are shown in Supplementary Table-S1). The metabolic peculiarities
- Hematology of the University of Rome Tor Vergata. PML::RARα presence locytes (EP/P-N7) (Fig. 1A and Supplementary Table-S2).
- was >60% in all patients. BM-MNCs isolated from healthy individuals were ylation/OXPHOS), mitochondrial respiration rate than normal
- number 24.24 CET2 ptv. Details on CD34+ hematopoietic progenitors cytes (EP/P-N13) and NBM (Fig. 1B and Supplementary Table-S2).
- antibodies used are reported in Supplementary Table S4. expression levels of these enzymes are significantly higher in APL
- patients described in Supplementary Table-S1. B Effects of 1 µM ATO treatment for 4 h in combination or not with 1 µM AKT inhibitor (Inhibitor
- VIII) for 30 min on the glycolytic activity in Fresh blasts from one APL patient (n° 8, Supplementary Table-S1) and C NB4 cells. Histograms
- AKT and p-AKT308 protein expression levels in (left) fresh blasts from an APL patient (n° 8, Supplementary Table-S1), (right) NB4 cells
- granulocytes; and primary APL blasts isolated from two patients with the XF Myto Fuel Flex Test (N° 4 and 5 from Supplementary Table S1).
- constant following PML::RARα degradation induced by ATO As shown in Fig. 1C-rigth and Supplementary Table-S3, PML::RARα
- increase of basal glycolysis in ATO treated PML::RARα+ cells, (LCFA: 63 ± 20% vs. glucose: 5 ± 7% and glutamine: 5 ± 7%)
- glycolysis, which was further decreased by AKT inhibition needs when the other pathways are inhibited (LCFA: 35 ± 21% vs.
- (Supplementary Fig.-S2A and S2B). To note that, in the absence pyruvate: 51 ± 30% and glutamine: 36 ± 17%) (Fig. 3A). Of note, as
- mentioned before, glycolysis enzymes are present and, once primary blasts from seven APL patients’, 68% ± 14 of the ATP was
- subsequent pyruvate scarcity must be the cause of the inability to 49% ± 22 of the ATP was produced by OXPHOS and 49% ± 22 by
- blot and correspond to those in Supplementary Table S1. Protein expression was quantified by densitometric analysis and normalized to β-
- These results indicate that the APL patients’ blasts rely mainly n = 11; AML 0.7 ± 0.3, n = 43, p = 0.4) (Supplementary Fig. S4B);
- These data let us hypothesize a major involvement of the Krebs’ APL blasts: SLC22A16 mRNA (APL: 57 ± 27, n = 17; AML 17 ± 15,
- Thus, we studied, using mass spectrometry, the levels of the 1.2 ± 0.48), n = 15; AML: 0.7 ± 0.3, n = 13, p = 0.04; NBM
- intermediates of the TCA, acylcarnitines, intermediates of Urea 0.1 ± 0.03, n = 3, p = 0.03 (Fig. 4C right). The expression of
- that, as a consequence, would reduce fatty acids synthesis fit in a cells. Notably, cleaved caspase-3 and PARP were detectable after
- cells: PDHA1 mRNA (APL: 0.7 ± 0.5, n = 11; AML 0.9 ± 0.4, n = 43, confirm that PML::RARα enhances mitochondrial depolarization
- indicating MCL-1 inhibition by AZA as a possible mean to scriptional activity. Oncotarget. 2016;7:66386–97.
- apoptosis: pharmacological inhibition of autophagy with NH4Cl affecting both the rearranged and the unrearranged PML alleles in refractory
- of FGFR3-TACC3 rearrangement in hematological malignancies with numerical 57. Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, et al.
Methods (brief)
- therapies in resistant or relapsed APL patients. We analyzed cell metabolism in primary samples from seven APL patients,
- patients’ samples, individuated two APL metabolic subtypes described in Supplementary Methods.
- subclones carrying new phenotypes that have been found significant samples from 7 APL patients (molecular and clinical characteristics
- resistant clones, will provide the mean to identify new therapeutic culture. Neutrophilic precursors were collected on day 7 (N7,
- Patient samples and controls observed in EP/P-N13 and NBM cells. However, APL blasts showed
- Bone marrow (BM) mononuclear cells (MNC) were collected from 7 lower basal glycolysis (p = 0.001), lower glycolytic capacity
- B Percentage of Glycolytic and mitochondrial ATP production in APL and AML patient’s samples measured using the ATP rate assay. Statistical
- (control) and PR9 (PML::RARα+) cells cells from two independent biological replicates, as determined by mass spectrometry. A, right
- PR9 (PML::RARα+) cells, measured by mass spectrometry from one biological replicate. B, right Intracellular acylcarnitine profiles in MT
- normal bone marrow (NBM) cells. C, right Protein expression levels of SLC22A16 (CT2), analyzed by Western blot in the same samples.
- Thus, we studied, using mass spectrometry, the levels of the 1.2 ± 0.48), n = 15; AML: 0.7 ± 0.3, n = 13, p = 0.04; NBM
- ATO resistant, (ATOR) Clone #2 exhibited inferior basal OXPHOS observed in normal promyelocytes. Patients’ samples from other
-
- Seo W, Silwal P, Song IC, Jo EK. The dual role of autophagy in acute myeloid experiments in PR9-MT cells, as well as the Western blot experiments on patient samples.
- myelocytic leukemia: synergistic in vitro antitumor effects with hypomethylating experiments. STu performed the mass spectrometry experiments. STr, MD, and TO
- agents or high-dose vitamin C. J Pharm Exp Ther. 2021;377:385–97. characterized APL patient samples. RP and PN obtained patient samples and updated the
-
- Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of clinical data. GC and AMC provided cord blood samples and carried out the differentiation
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- Arsenic
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