YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Cellular and Molecular State of Myeloid Leukemia Stem Cells.

Leukemia stem cells (LSCs) are leukemia-initiating population with the capacity to self-renew, differentiate, and stay quiescent. Human hematopoietic malignancies such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are derived from this cell population. LSCs are also responsible for disease relapse due to its resistance to drug treatment. This rare cell population is phenotypically and functionally heterogeneous. Increasing evidence indicates that this heterogeneous cellular state of LSCs might determine the different drug sensitivity and is the major reason for disease relapse. In here, focusing on myeloid leukemia stem cells, we describe the biological features including cellular and molecular state, heterogeneity of LSCs, and the dynamic cross talk between LSCs and bone marrow microenvironment. These specific features of LSCs highlight the dynamic cellular state of LSCs, and further exploring on it might provide potential therapeutic targets that are important for eliminating LSCs.

Metabolic dependencies of acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy primarily driven by an immature population of AML cells termed leukemia stem cells (LSCs) that are implicated in AML development, chemoresistance, and relapse. An emerging area of research in AML focuses on identifying and targeting the aberrant metabolism in LSCs. Dysregulated metabolism is involved in sustaining functional properties of LSCs, impeding myeloid differentiation, and evading programmed cell death, both in the process of leukemogenesis and in response to chemotherapy. This review discusses recent discoveries regarding the aberrant metabolic processes of AML LSCs that have begun to change the therapeutic landscape of AML.

[Effects of Balanced Fertilization and Straw Mulching on Soil Nutrients and Stoichiometry in Purple Soil Slope].

To explore the effects of long-term balanced fertilization and straw mulching on soil nutrients and stoichiometric ratios in purple soil sloping cropland, nine plots (length 7 m×width 3 m) were established in Dianjiang County as the research sample area of long-term farmland nitrogen and phosphorus loss monitoring. The following three treatments were set up:conventional mode (CK), balanced fertilization mode (M1), and balanced fertilization+straw mulching mode (M2), with three replications for each treatment to compare the contents of carbon (C), nitrogen (N), phosphorus (P), and potassium (K) and their stoichiometric changes under different treatments from 2018 to 2020. The results showed:K contents showed significant differences among the three treatments in 2018, in the order of CK>M2>M1. NO3--N and NH4+-N contents showed significant differences among the three treatments in 2019, both in the order of M1>M2>CK. Other nutrient contents showed no significant difference among different treatments each year. Soil C and N contents showed non-significant differences among different years. The total K contents of CK, M1, and M2 in 2018 were significantly higher than that in other years and were 78.26% and 98.79%, 19.13% and 35.4%, and 54.49% and 41.76% higher than that in 2019 and 2020, respectively. The total P content in the CK and M2 treatments decreased with years, and that of CK and M2 in 2018 was 20.29% and 10.67% and 39.68% and 17.33% higher than that in 2019 and 2020, respectively. The available potassium (AK) content of the three treatments showed non-significant differences among different years, whereas the contents of nitrate nitrogen (NO3--N), ammonium nitrogen (NH4+-N), and available phosphorus (AP) showed significant differences among the different treatments, with all being the highest in 2020. Soil C:P, C:K, N:P, N:K, and P:K ratios of each treatment showed significant differences among different years (P<0.05). Soil C:K, N:K, and AN:AP ratios all showed significant differences among different fertilization modes in 2018 and 2019, respectively (P<0.05). There was a significantly linearly positive relationship between soil C and N concentration and soil P and K concentration. There were very significant linear positive correlations between soil C:K and C:P, N:K, N:P, and P:K; N:K with C:P, P:K, and N:P; and N:P with C:P, N:P, and C:P. Soil P concentration was highly significantly linearly negatively correlated with C:K and N:K ratios. There were significant positive correlations between soil NO3--N, NH4+-N, AN:AP, and AN:AK; NH4+-N, AN:AP, and AN:AK; and AN:AP and AN:AK. The results suggested that balanced fertilization and straw mulching was a more suitable management mode for purple soil sloping cropland.

Soil water repellency and micro-aggregate fractions in response to crop growth periods in a sloping cropland subjecting to long-term fertilization management.

Fertilization management and crop growth can affect soil water repellency (SWR) through altering other soil properties such as micro-aggregate, soil organic carbon (SOC) and total nitrogen (TN). However, the extents and magnitudes of these effects remain unclear. This study aimed to determine the effects of different crop growth periods and long-term fertilization managements on SWR and selected soil physicochemical properties and their linkages. Soil samples were collected from agricultural plots experiencing different maize growth periods (ES, elongation stage; TS, tasseling stages; FS, filling stage; and MS, maturity stage) and fertilization managements (CK, no fertilizer with downslope cultivation; T1, combined manure and chemical fertilizers with downslope cultivation; T2, chemical fertilizer with downslope cultivation; T3, 1.5-fold chemical fertilizer with downslope cultivation; T4, chemical fertilizer with contour cultivation) in a representative sloping cropland with Entisols, southwest China. SWR, micro-aggregate fractions, and other physiochemical properties like soil organic carbon (SOC) and total nitrogen (TN) were determined. Results showed that SWR increased by 64.93% in T1 than in CK, and fertilization managements (i.e., T1, T2, T3, and T4) markedly increased soil 1000-250 µm fraction by 34.50-50.74% and reduced 250-50 µm fraction by 22.95-48.87% than CK did. SWR was 27.35%-78.74% higher in ES than that in other growth periods. The highest soil 250-50 fractions (30.80%) and the lowest <50 µm fractions (43.95%) both appeared in TS. SOC was both differed by fertilization management and growth period, while TN was only affected by the former. SWR was predicted well by TN alone. Our results indicate that long-term fertilizer application enhances SWR and have great significance for optimizing sustainable agricultural management in the similar sloping croplands.

Differential m6A RNA landscapes across hematopoiesis reveal a role for IGF2BP2 in preserving hematopoietic stem cell function.

N6-methyladenosine (m6A) on mRNA plays critical roles in various cellular processes. However, the landscape and dynamics of m6A modification in hematopoietic system remain unknown. Here, we delineate a comprehensive m6A landscape across hematopoietic hierarchy and uncover that IGF2BP2 is required for preserving the function of hematopoietic stem cells (HSCs). Our data reveal a cell-type-specific m6A landscape in hematopoiesis. m6A modifications arise mostly in the early stage of hematopoiesis and prefer to play distinct roles for determining mRNA fates in HSCs and committed progenitors. Mechanistically, increased m6A-IGF2BP2 expression controls transcriptional state and maintenance of HSCs. IGF2BP2 deficiency induces quiescence loss and impairs HSC function. Moreover, IGF2BP2 loss increases mitochondrial activity of HSCs by accelerating Bmi1 mRNA decay, leading to de-repression of mitochondria-related genes. Collectively, our results present a fascinating portrait of m6A modification of hematopoietic hierarchy and reveal a key role of IGF2BP2 in maintaining HSC function by restraining mitochondrial activity.

RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis.

N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.

Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis.

N6-methyladenosine (m6A) is a commonly present modification of mammalian mRNAs and plays key roles in various cellular processes. m6A modifiers catalyze this reversible modification. However, the underlying mechanisms by which these m6A modifiers are regulated remain elusive. Here we show that expression of m6A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesis of human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemia stem cell (LSC) function but is dispensable for normal hematopoiesis. Mechanistically, KDM4C regulates ALKBH5 expression via increasing chromatin accessibility of ALKBH5 locus, by reducing H3K9me3 levels and promoting recruitment of MYB and Pol II. Moreover, ALKBH5 affects mRNA stability of receptor tyrosine kinase AXL in an m6A-dependent way. Thus, our findings link chromatin state dynamics with expression regulation of m6A modifiers and uncover a selective and critical role of ALKBH5 in AML that might act as a therapeutic target of specific targeting LSCs.

Molecular mechanisms for stemness maintenance of acute myeloid leukemia stem cells.

Human acute myeloid leukemia (AML) is a fatal hematologic malignancy characterized with accumulation of myeloid blasts and differentiation arrest. The development of AML is associated with a serial of genetic and epigenetic alterations mainly occurred in hematopoietic stem and progenitor cells (HSPCs), which change HSPC state at the molecular and cellular levels and transform them into leukemia stem cells (LSCs). LSCs play critical roles in leukemia initiation, progression, and relapse, and need to be eradicated to achieve a cure in clinic. Key to successfully targeting LSCs is to fully understand the unique cellular and molecular mechanisms for maintaining their stemness. Here, we discuss LSCs in AML with a focus on identification of unique biological features of these stem cells to decipher the molecular mechanisms of LSC maintenance.

[Advances of Researches on Anti-phage Mechanisms of Host].

Phages also known as bacteria viruses, are recognized as the most abundant and diverse microbes. This diversity is adapting to the selective pressures such as the prevalence of the phage resistance mechanisms of bacteria. Phages invade and lyse bacterial through six steps (adsorption, injection, replication, transcription translation, assemble, release). Bacteria evolve to many anti-phage mechanisms to avoid phage infection and lysis. This paper focus on a variety of anti-phage mechanisms of bacteria.

Complete Genome Sequence of the Salmonella enterica Serovar Paratyphi A Bacteriophage LSPA1 Isolated in China.

The bacteriophage LSPA1 was isolated from hospital sewage (Kunming, China), and lytic activity was demonstrated against the Salmonella enterica serovar Paratyphi A CMCC50973 strain. This bacteriophage has a 41,880-bp double-stranded DNA (dsDNA) genome encoding 58 coding sequences (CDSs) and belongs to the family Siphoviridae.