Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations.

Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic patterns associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.

Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

Insight into the mechanism and outcoupling enhancement of excimer-associated white light generation.

Fundamental insight into excimer formation has been gained by using 9,10-bis[4-(9-carbazolyl)phenyl]anthracene] (Cz9PhAn) as a probe. Cz9PhAn exhibits a highly emissive blue fluorescence in solution and is found to emit a panchromatic white light spectrum (400-750 nm) in film, powder and single crystal, in which an additional excimer band appears at ∼550 nm. Detailed structural analyses, emission relaxation dynamics and a theoretical approach conclude the formation of an anthracene*/phenyl ring excimer through an overlap between π* (anthracene) and π (phenyl ring) orbitals in a face-to-edge stacking orientation. The rate of excimer formation is determined to be 2.2 × 109 s-1 at room temperature, which requires coupling with lattice motion with an activation energy of 0.44 kcal mol-1. Exploiting Cz9PhAn as a single emitter, a fluorescent white organic light emitting diode (WOLED) is fabricated with a maximum external quantum efficiency (ηext) of 3.6% at 1000 cd m-2 (4.2 V) and Commission Internationale de L'Eclairage (CIE) coordinates of (0.30, 0.33). The white-light Cz9PhAn reveals a preferred orientation of the transition dipole moment in the emitting layer to enhance light outcoupling. This non-doped, single component (Cz9PhAn) WOLED greatly reduces the complexity of the fabrication process, rendering a green and cost-effective alternative among the contemporary display/lighting technologies.

Excited-State Conformational/Electronic Responses of Saddle-Shaped N,N'-Disubstituted-Dihydrodibenzo[a,c]phenazines: Wide-Tuning Emission from Red to Deep Blue and White Light Combination.

A tailored strategy is utilized to modify 5,10-dimethylphenazine (DMP) to donor-acceptor type N,N'-disubstituted-dihydrodibenzo[a,c]phenazines. The representative compounds DMAC (N,N'-dimethyl), DPAC (N,N'-diphenyl), and FlPAC (N-phenyl-N'-fluorenyl) reveal significant nonplanar distortions (i.e., a saddle shape) and remarkably large Stokes-shifted emission independent of the solvent polarity. For DPAC and FlPAC with higher steric hindrance on the N,N'-substituents, normal Stokes-shifted emission also appears, for which the peak wavelength reveals solvent-polarity dependence. These unique photophysical behaviors are rationalized by electronic configuration coupled conformation changes en route to the geometry planarization in the excited state. This proposed mechanism is different from the symmetry rule imposed to explain the anomalously long-wavelength emission for DMP and is firmly supported by polarity-, viscosity-, and temperature-dependent steady-state and nanosecond time-resolved spectroscopy. Together with femtosecond early dynamics and computational simulation of the reaction energy surfaces, the results lead us to establish a sequential, three-step kinetics. Upon electronic excitation of N,N'-disubstituted-dihydrodibenzo[a,c]phenazines, intramolecular charge-transfer takes place, followed by the combination of polarization stabilization and skeletal motion toward the planarization, i.e., elongation of the π-delocalization over the benzo[a,c]phenazines moiety. Along the planarization, DPAC and FlPAC encounter steric hindrance raised by the N,N'-disubstitutes, resulting in a local minimum state, i.e., the intermediate. The combination of initial charge-transfer state, intermediate, and the final planarization state renders the full spectrum of interest and significance in their anomalous photophysics. Depending on rigidity, the N,N'-disubstituted-dihydrodibenzo[a,c]phenazines exhibit multiple emissions, which can be widely tuned from red to deep blue and even to white light generation upon optimization of the surrounding media.

A new insight into the chemistry of iridium(III) complexes bearing phenyl phenylphosphonite cyclometalate and chelating pyridyl triazolate: the excited-state proton transfer tautomerism via an inter-ligand PO-H···N hydrogen bond.

Treatment of [IrCl3(tht)3], where tht = tetrahydrothiophene, with two equiv. of phenyl diphenylphosphinite (pdpitH) gave [Ir(pdpitH)(pdpit)(tht)Cl2] (1), which on further reaction with 3-t-butyl-5-(2-pyridyl)-1,2,4-triazole (bptzH) and NaOAc using a one-pot reaction afforded [Ir(pdpit)2(bptz)] (2). In sharp contrast, the reaction of [IrCl3(tht)3], pdpitH, and bptzH in the presence of a stronger base, Na2CO3, afforded a phenyl phenylphosphonite (pppo)-containing Ir(III) complex [Ir(pdpit)(pppo)(bptz)] (3) that reveals a strong PO-H-N inter-ligand hydrogen bond (H-bond), as evidenced by the single crystal X-ray structural analysis. For confirmation, addition of diazomethane to a diethylether solution of 3 led to the isolation of two methylated Ir(III) isomeric complexes, i.e. [Ir(pdpit)(pppoMe)(bptz)] (4) and [Ir(pdpit)(pppo)(bptzMe)] (5), possessing either a PO-Me or N-Me bonding fragment, respectively. The absorption spectrum of 3 in CH2Cl2 resembles that of 4, implying the dominant PO-H character in solution. Despite the prevailing PO-H character both in the solid crystal and in solution, its corresponding emission resembles that of 5, leading us to propose a mechanism incorporating the excited-state inter-ligand proton transfer (ESILPT) from PO-H to N-H isomeric form via the pre-existing PO···H···N hydrogen bond. The thermodynamics of proton transfer tautomerism are discussed on the basis of absorption/emission spectroscopy in combination with computational approaches; additional support is given by the relationship between emission pattern versus the position of protons and methyl substituents. The results demonstrate for the first time a paradigm of excited-state proton transfer for the transition metal complexes in the triplet manifold.

Water-catalyzed excited-state proton-transfer reactions in 7-azaindole and its analogues.

The mechanism of the water-catalyzed excited-state proton-transfer (ESPT) reaction for 7-azaindole (7AI) has long been investigated, but there are some controversial viewpoints. Recently, owing to the superiority of sensing biowaters in proteins by a 7AI analogue, 2,7-diazatryptophan, it is timely to reinvestigate water-catalyzed ESPT in 7AI and its analogues in an attempt to unify the mechanism. Herein, a series of 7AI analogues and their methylated derivatives were synthesized to carry out a systematic study on pKa, pKa*, and the associated fluorescence spectroscopy and dynamics. The results conclude that all 7AI derivatives undergo water-catalyzed ESPT in neutral water. However, for those derivatives with -H (7AI) and a electron-donating substituent at C(3), they follow water-catalyzed ESPT to form an excited N(7)-H proton-transfer tautomer, T*. T* is rapidly protonated to generate an excited cationic (TC*) species. TC* then undergoes a fast deactivation to the N(1)-H normal species in the ground state. Conversely, protonation in T* is prohibited for those derivatives with an electron-withdrawing group at the C(2) or C(3) or with the C(2) atom replaced by an electron-withdrawing nitrogen atom (N(2) in, e.g., 2,7-diazatryptophan), giving a prominent green T* emission. Additional support is given by the synthesis of the corresponding N(7)-CH3 tautomer species, for which pKa* of the cationic form, that is, the N(7)-CH3N(1)-H(+) species, is measured to be much greater than 7.0 for those with electron-donating C(3) substituents, whereas it is lower than 7.0 upon anchoring electron-withdrawing groups. For 7AI, the previously missing T* emission is clearly resolved with a peak wavelength at 530 nm in the pH interval of 13.0-14.3 (H- 14.2).