Take stock: A selection of Blood Research Highlights of June 11, 2020

Transcription factor ATF4 activation BCL11A transcription to silent fetal hemoglobin expression Fetal hemoglobin reactivation remains a critical goal for the treatment of patients with sickle cell disease and beta-thalassemiaPrevious researchers have found that fetal gamma-globin gene silencing requires the involvement of red blood cell-specific eIF2 alpha kinase HRI, suggesting that HRI may provide a pharmacological target for raising fetal hemoglobin levelsRecently, researchers identified the transcription factor ATF4, a known HRI-regulated protein, as a new gamma-bead protein regulatory factor through CRISPR-CAS9-oriented human red blood cell loss screeningATF4 directly stimulates the transcription of BCL11A by binding with the enhancers of the gamma-pearl transcription inhibitor BCL11A and promoting the enhanced child-starter contact of BCL11ANotably, HRI defective mice showed normal Bcl11a levels, indicating species selective regulation, as explained by the researchers by proving that there is a similar ATF4 sequence on the Bcl11a enhancer in mice that is largely optional2Venetoclax combined LDAC treatment for AML patients who are not suitable for intensive chemotherapy currently has limited effective treatment options for patients with acute myeloid leukemia (AML) who are unable to tolerate intensive chemotherapyIn a recent phase 3 clinical trial, 211 newly diagnosed AML patients over the age of 18 were recruited who did not apply intensive chemotherapyRandomly divided into venetoclax group (143 persons) or placebo group (68 people), 28 days of one course, both groups for the first 10 days of each course of the combined low dose of acesporine (LDAC)The primary endpoint is the overall survival period (OS);The median age of the patients was 76 years old, 38% of the patients were secondary AML, and 20% of the patients were previously treated with the hypoxmethylation agent (HMA)The main analysis showed that the risk of death was reduced by 25% (risk ratio compared to .75) in the venetoclax group compared to LDAC alone, with the median OS in the two groups being 7.2 months and 4.1 months, respectivelyAnalysis after 6 months of additional follow-up showed that the median OS in the venetoclax group was 8.4 months (HR 0.70)Cr/CRi for venetoclax combined LDAC therapy was 48%, compared with 13% for LDAC treatment aloneAdverse reactions at level 3 and above were (Ven vs LDAC): febrile neutrophil reduction (32% vs 29%), neutrophil reduction (47% vs16%) and platelet reduction (45% vs 37%) The aromatase involved in IMiDs induced platelet reduction immunomodulation drug (IMiDs) is a key drug for the treatment of chromosomal 5q deficiency multiple myeloma and myelomication abnormal syndrome IMiD plays its multi-effect by raising new substrates to Thee3 connecting enzyme cereblon Recently, researchers found that IMiD severely affects platelet formation by inhibiting the transmission of self-secreted estradiol signals in human giant nuclear cells, a key step in functional platelet production In addition, the researchers identified aromatase, an enzyme indispensable in estradiol biosynthesis, as a new type of substrate for cereblon IMiDs promote the collection of aromatase to cereblon, causing aromatase to degrade by protease-dependent methods Finally, in the bone marrow of patients with multiple myeloma that was treated with IMiDs that led to platelet reduction, the aromatase significantly degraded A lot of information about the cancer-causing NTRK gene activation mutation new target cancer neurotrophic receptor tyrosine kinase (NTRK) gene is obtained by identifying and characterizing the activation of multiple tumor types Given that these receptors are expected to be the target of cancer treatment Recently, researchers identified ntRK2 and NTRK3 gene mutations by deep sequencing of 185 patients with hematologic malignancies Ten patients carried TNRK2 or TNRK3-point mutations In these patients, the researchers identified a total of nine unique point mutations Of these nine mutations, four tumor-inducing mutations were identified through cytokine non-dependent cell tests: NTRK2 A203T, NTRK2 R458G, NTRK3 E176D, and NTRK3 L449F This study shows that these mutations have the potential to promote downstream survival signals and the occurrence of leukemia Especially with out-of-cell (NTRK2 A203T and NTRK3 E176D) transmembrane (NTRK3 L449F) domain 3 mutations increase the receptor's dipolymeract and cell surface abundance The fourth mutation, NTRK2R458G, is located in the near-membrane domain and activates TrkB through non-classical mechanisms, which may involve altering the mutation receptor and the oil in the surrounding environment MKL1 Defective Severe Immune Dysfunction Giant Young Cell Leukemia 1 (MKL1) promotes the regulation of basic cellular processes, including kinetic cytoskeleton dynamics, by combining the activation of serum reaction factors Recently, the first case of MKL1 defect in human patients leading to a new primary immunodeficiency was discovered The researchers reported on a second family, and the brothers both carried the MKL1 gene's pure-shifting code variant Brother died in her infancy from severe pneumonia combined with copper-green pseudomonasacell infection and poor wound healing The younger brother had a pre-transplant shortly after birth The immunodeficiency was shown as obvious myoglobin polymerization defects, and MKL1 defects of neutrophils decreased significantly to the movement and chemochemical response In addition to the lack of MKL1, the researchers' proteomic and transcriptional studies of patients' neutrophils found that actin and several kinetic proteins were lowered, confirming the role of MKL1 as transcription synergy regulators When suboptimal neutrophils are activated, the departicle action is enhanced and the reactive oxygen is produced normally Neutros adhere normally, but do not diffuse properly The latter can explain the adhesion and trans-endothelial migration failures observed under flow conditions No significant phagocytosis and bacterial culling disorders were observed Macrophages from mononucleoblasts also showed normal phagocytosis; Non-hematopoietic fibroblasts exhibited myocellular differentiation disorder, but their migration and silk-like actin (F-actin) levels were normal, which may be related to MKL2's replacement mechanism, which MKL2 did not express in neutrophils Source: MedSci Original