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Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 ( FLT3 ) and rat sarcoma viral oncogene homolog ( RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3- ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain ( FLT3 -TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-α (40%) mutations. However, epigenetics-modifying gene ( DNMT3a , TET2 and IDH1/2 ) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3 -ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them ( P =0.001). Moreover, the high frequency of FLT3 -ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations ( P <0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3 -ITD, leading to resistance to therapy and relapse.

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter ( P =0.0006) and cumulative incidence of relapse (CIR) significantly higher ( P =0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3 -ITD ( FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P =0.0010; CIR: P =0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS ( P =0.0007). In stratification based on FLT3 -ITD and CEBPA status and ‘simplified analysis of co-mutations’ using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P =0.0002. CIR: P <0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor ( P =0.355), but was a factor when using MB-PCR ( P =0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses ( P =0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML.

Investigating Pacific meridional modes (PMMs) without the influence of tropical Pacific variability is technically difficult if based on observations or fully coupled model simulations due to their overlapping spatial structures. To confront this issue, the present study investigates both the North PMM (NPMM) and South PMM (SPMM) in terms of their associated atmospheric forcing and response processes based on a mechanically decoupled climate model simulation. In this experiment, the climatological wind stress is prescribed over the tropical Pacific, which effectively removes dynamically coupled tropical Pacific variability (e.g., El Niño–Southern Oscillation). Interannual NPMM in this experiment is forced not only by the North Pacific Oscillation but also by a North Pacific tripole (NPT) pattern of atmospheric internal variability, which primarily forces decadal NPMM variability. Interannual and decadal variability of the SPMM is partly forced by the South Pacific Oscillation. In turn, both interannual and decadal NPMM variability can excite atmospheric teleconnections over the Northern Hemisphere extratropics by influencing the meridional displacement of the climatological intertropical convergence zone throughout the whole year. Similarly, both interannual and decadal SPMM variability can also excite atmospheric teleconnections over the Southern Hemisphere extratropics by extending or shrinking the climatological South Pacific convergence zone in all seasons. Our results highlight a new poleward pathway by which both the NPMM and SPMM feed back to the extratropical climate, in addition to the equatorward influence on tropical Pacific variability.

To elucidate the unique seasonality in the coupled system of the subtropical Mascarene high and low-level clouds, the present study compares wintertime cloud radiative impacts on the high with their summertime counterpart through coupled and atmospheric general circulation model simulations. Acomparison of a fully coupled control simulation with another simulation in which the radiative effects of low-level clouds are artificially switched off demonstrates that the low-cloud effect on the formation of the Mascarene high is much weaker in winter. Background climatology plays an important role in this seasonality of the Mascarene high reinforcement. Relative to summer, the suppression of deep convection due to low-level clouds that acts to reinforce the high is much weaker in winter. This arises from 1) seasonally lower sea surface temperature in concert with the smaller sea surface temperature reduction due to the deeper ocean mixed layer and the weaker cloud radiative effect under weaker insolation and 2) seasonally stronger subtropical subsidence associated with the Hadley circulation in winter. As verified through atmospheric dynamical model experiments, enhanced cloud-top radiative cooling by low-level clouds acts to reinforce the wintertime Mascarene high in comparable magnitude as in summer. The present study reveals that the self-sustaining feedback with low-level clouds alone is insufficient for replenishing the full strength of the wintertime Mascarene high. This implies that another internal feedback pathway and/or external driver must be operative in maintaining the wintertime high.

Dendritic cells (DC) are mediators between innate and adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between “Conventional” DCs (cDCs) and plasmacytoid DCs (pDCs). Activating mutations of FLT3, including Internal Tandem Duplication (FLT3-ITD), are associated with poor prognosis for acute myeloid leukemia (AML) patients. Having a shared myeloid lineage it can be difficult to distinguish bone fide DCs from AML tumor cells. To date, there is little information on the effects of FLT3-ITD in DC biology. To further elucidate this relationship we utilized CITE-seq technology in combination with flow cytometry and multiplex immunoassays to measure changes to DCs in human and mouse tissues. We examined the cDC phenotype and frequency in bone marrow aspirates from patients with AML to understand the changes to cDCs associated with FLT3-ITD. When compared to healthy donor (HD) we found that a subset of FLT3-ITD+ AML patient samples have overrepresented populations of cDCs and disrupted phenotypes. Using a mouse model of FLT3-ITD+ AML, we found that cDCs were increased in percentage and number compared to control wild-type (WT) mice. Single cell RNA-seq identified FLT3-ITD+ cDCs as skewed towards a cDC2 T-bet - phenotype, previously shown to promote Th17 T cells. We assessed the phenotypes of CD4 + T cells in the AML mice and found significant enrichment of both Treg and Th17 CD4 + T cells in the bone marrow and spleen compartments. Ex vivo stimulation of CD4 + T cells also showed increased Th17 phenotype in AML mice. Moreover, co-culture of AML mouse-derived DCs and naïve OT-II cells preferentially skewed T cells into a Th17 phenotype. Together, our data suggests that FLT3-ITD+ leukemia-associated cDCs polarize CD4 + T cells into Th17 subsets, a population that has been shown to be negatively associated with survival in solid tumor contexts. This illustrates the complex tumor microenvironment of AML and highlights the need for further investigation into the effects of FLT3-ITD mutations on DC phenotypes and their downstream effects on Th polarization.

Acute myeloid leukemia (AML) is characterized by a complex interplay between genomic alterations, aberrant hematopoiesis, and immune evasion. The aryl hydrocarbon receptor (AHR) pathway is a critical player in this phenomenon determining the fate of stem cell differentiation as well as dictating immune cell development and function. Despite this critical connection, little is known about how AHR regulates the immune microenvironment in AML. We performed a retrospective study examining the pre-treatment effect of immune cell numbers (T and NK cells) in the bone marrow and their impact on overall survival in AML patients undergoing 7+3 induction chemotherapy. Utilizing flow cytometry and both bulk and single-cell RNA sequencing of AML patient samples, we characterized the immune signature of blast cells and the influence of AHR on the immune microenvironment. Lastly, we performed functional studies to determine impact of pharmacological and genomic AHR inhibition on NK cell function. Higher bone marrow NK cell percentage in ND-AML correlated with poorer OS and expression of HLA-E on leukemic blasts. AHR upregulation was associated with HLA-E expression on blasts and an innate immune resistant signature defined by upregulation of key cytokine pathways, interferon gamma (IFN-g) pathway, and MHC class I/II as well as impaired NK cell profiles. High AHR expression in AML was associated with monocytic maturation and discrepant MHC class I/II profiles. Pre-treatment of blasts with an AHR inhibitor (AHRi) prior to NK cell killing assay downregulated key checkpoint molecules, including HLA-E, and key IFN-g signaling transcription factors (STAT1, IRF1) and led to enhanced NK cell killing among multiple FAB subsets in AML. The data support targeting the AHR pathway as a dual tumor intrinsic and immune targeting therapeutic strategy for AML, particularly in combination with NK cellular therapy.

Background In the global ARASENS study (NCT02799602), darolutamide plus androgen‐deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57–0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone‐sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants. Methods Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival. Results The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50–1.64), despite 85% of patients in the placebo group receiving subsequent life‐prolonging therapy. Darolutamide prolonged time to castration‐resistant prostate cancer (HR 0.31; 95% CI 0.17–0.55). Treatment‐emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population. Conclusion In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients. In Japanese patients with metastatic hormone‐sensitive prostate cancer (mHSPC) who participated in the global phase 3 ARASENS study, darolutamide in combination with androgen‐deprivation therapy (ADT) and docetaxel showed favorable trends in efficacy and tolerability over placebo plus ADT and docetaxel, with no new safety concerns. The outcomes were consistent with the findings in the overall study population and support the use of darolutamide in combination with ADT and docetaxel in Japanese patients with mHSPC as a new standard of care.