Acute Lymphoblastic Leukemia (ALL) is a disease caused by abnormal differentiation of lymphocytes in the early stage and malignant proliferation. The main pathological manifestation is that a large number of blast cells accumulate in the bone marrow, destroying the normal hematopoietic microenvironment of the bone marrow, resulting in symptoms of anemia, infection, and hemorrhage, and extramedullary infiltration can occur in the late stage. Therefore, it is necessary to further explore the molecular mechanism of ALL in order to find effective drugs for the treatment of ALL as soon as possible. CD BioSciences provides precise in vivo transfection services of lymphocytes to assist in the study of the molecular functions of acute lymphocytic leukemia-related genes.

Figure 1. Acute Lymphocytic Leukemia.( Fredric Samson Kirubakaran Sakthiraj, et al.; 2021)

Target Genes Delivered in vivo in Acute Lymphocytic Leukemia

Through years of continuous development and research of molecular biology techniques, TP53, IL-7/IL-7R, GATA3, DNMT3A, IKZF1, NOTCH1, CRLF2 and other mutant genes have been discovered in acute lymphocytic leukemia.

TP53

TP53 is the most common mutation in human cancers. The gene is located on chromosome 17 and encodes a nuclear phosphorylation protein that is involved in DNA repair or metabolic processes and can induce cell cycle arrest, senescence, and apoptosis. TP53 mutations can lead to cell cycle disorders, genome instability, and uncontrolled cell proliferation, which occur in almost all types of cancer, and are more common in ovarian cancer, esophageal cancer, and colorectal cancer. Using NGS technology to analyze TP53 mutations and cytogenetics Correlation analysis found that TP53 mutation was significantly associated with hypodiploidy, MYC translocation and complex karyotype. The results of the survival analysis of ALL patients showed that the overall survival of mutation patients was significantly shortened.

IL-7/IL-7R

IL-7 and IL-7R play an important role in the development of B cells. The combination of the two promotes the proliferation and survival of precursor cells, and the transformation of progenitor B cells into pre-B cells. During B cell development, IL-7Rα signaling is tightly regulated and, in conjunction with key transcription factors such as PAX5, EBF1 or IKAROS, and pre-BCR, regulates Ig gene rearrangements. Excess or underexpression of IL-7R leads to abnormal B-cell development, and its absence leads to severe combined immunodeficiency. IL-7R polymorphisms have been shown to be risk factors for many autoimmune diseases or those involving hyperimmune and inflammatory responses. Using NGS technology to sequence the bone marrow samples of patients with acute T lymphoblastic leukemia (TALL), it was found that gene mutations related to the IL-7R pathway occurred in 28% of patients.

GATA3

GATA3 encodes a key transcription factor in the development and differentiation of T and B cells. Studies have shown that it can be expressed in pluripotent hematopoietic stem cells (HSC), but its role has not yet been clarified. Enhanced expression of GATA3 suppresses maturation of natural killer cells and CD8+ T cells. More and more evidence shows that its mutation is related to the occurrence and prognosis of breast cancer, Hodgkin's lymphoma, and ALL. Inherited mutations in GATA3 increase susceptibility to B-ALL in adolescents and adults.

DNMT3A

DNMT3A plays an important role in T cell development and T-ALL development, and can maintain the balance between HSC differentiation and self-renewal by controlling specific DNA methylation of gene expression programs. DNMT3A mutations have been found in a variety of hematological malignancies, such as acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, and mutations in this gene are generally considered to be preleukemic events. Studies have found that the loss of DNMT3A function and the enhancement of NOTCH1 function work together to promote the occurrence of T-ALL in mice.

IKZF1

IKZF1 gene is located on chromosome 7p12.2 and consists of 8 exons. The gene encodes the transcription factor IKAROS, which belongs to the zinc finger DNA-binding protein family related to chromatin remodeling. The expression of this protein is restricted to the fetal and adult blood system, and it acts as a regulator of lymphocyte differentiation. IKZF1 is associated with common variable immunodeficiency disease, congenital pure red cell aplasia and other diseases. In recent years, IKZF1 has been a star gene in leukemia-related research, and has been found to be a common gene alteration in Ph-like ALL.

NOTCH1

NOTCH1 gene is a member of highly conserved NOTCH gene family, located on chromosome 9q34.3, encoding NOTCH1 transmembrane protein. The Notch signaling pathway is involved in physiological processes such as embryonic development, cell growth, apoptosis, and differentiation, and plays an important role in lymphocyte differentiation, development, and proliferation. related. Mutations in this gene play a key role in the occurrence and progression of ALL, and are key regulators of human T-ALL. About 50% to 60% of T-ALL samples show NOTCH1 mutations.

CRLF2

CRLF2 is a protein-coding gene encoding cytokine receptor-like factor 2 (CRLF2), also known as thymic stromal lymphopoietin (TSLP) receptor. The CRLF2 subunit forms a heterodimeric complex with IL-7R to produce a functional receptor for TSLP, activates STAT3, STAT5, and JAK2 pathways, and controls processes such as cell proliferation and hematopoietic system development. About 5% to 10% of B-ALL, 50% of Ph chromosome-positive ALL, and 50% to 60% of ALL patients with Down syndrome (DS) have CRLF2 rearrangement, which often leads to leukemia cells Glucocorticoid sensitivity decreased.

In addition to the above genes, there are interesting acute lymphocytic leukemia-related genes that need to be explored and studied. Therefore, there is a need for an in vivo transfection system that can precisely target acute lymphocytic leukemia tissue and be taken up by tumor cells to function in vivo. The system can help researchers overcome various challenges encountered during in vivo transfection:

• Relevant molecular function studies can only be carried out in vitro, lacking important in vivo data;
• Using in vitro transfection system for in vivo transfection, the transfection efficiency is very low;
• The in vivo transfection system used is not specific to Acute lymphocytic leukemia tissues and cells, and is toxic to the body;
• The in vivo transfection system used cannot penetrate the Acute lymphocytic leukemia tissue into the tumor tissue;
• The nucleic acid load of the in vivo transfection system is low, and it is difficult to achieve the expected effect;
• Etc…

Our Advantage:

• We can provide an in vivo transfection system for Acute lymphocytic leukemia tissues and cells to achieve efficient transfection
• Our system can target multiple targets at the same time, improving targeting accuracy
• The in vivo transfection system has low toxicity to the body and is safe to use
• In vivo transfection system vectors can protect nucleic acids from degradation during in vivo delivery
• Persistent knockout effect in experimental animals after a single injection
• The system load is high, and the transfection needs of different doses can be completed
• Professional design and service team to provide you with reliable service and technical support
• Timely feedback of technical reports

CD BioSciences specializes in developing transfection systems and customizing transfection reagents for gene transfection using our core technologies. With our high-quality products and services, your transfection results can be greatly improved. If you can't find a perfect in vivo transfection system, you can contact us. We can provide one-to-one personal customization service.

References

1. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020, 395(10230):1146-1162.
2. Stengel A, et al.; TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis. Blood. 2014, 124(2):251-258.
3. Kim R, et al.; Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation. Leukemia. 2020, 34(7):1730-1740.
4. Afzaljavan F, et al.; GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients. Sci Rep. 2021, 11(1):1679.
5. Venugopal K, et al.; Alterations to DNMT3A in hematologic malignancies. Cancer Res. 2021, 81(2):254-263.
6. Pui CH, et al.; Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017, 17(8):464-470.
7. Armstrong F, et al.; NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood. 2009, 113(8):1730-1740.
8. Brown AL, et al.; Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome. Blood. 2019, 134(15):1227-1237.
9. Fredric Samson Kirubakaran Sakthiraj, et al.; Autonomous Leukemia Detection Scheme Based on Hybrid Convolutional Neural Network Model Using Learning Algorithm. Wireless Personal Communications. 2021, 126(2).

* For research use only. Not for use in clinical diagnosis or treatment of humans or animals.