Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding ofex vivoHSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner throughin vivofate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized forex vivoexpansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.

Background: Inducing apoptosis in cancer cells is an important step for the successful treatment of cancer patients. Bcl‐2 is an antiapoptotic protein which determines apoptosis by interacting with proapoptotic members of the Bcl‐2 family. Exome sequencing has identified Bcl‐2 and Bax missense mutations in more than 40 cancer types. However, a little information is available about the functional impact of each Bcl‐2 and Bax mutation on the pathogenesis of cancer.Methods: The mutational data from cancer tissues and cell lines were retrieved from the cBioPortal web resource. The 13 mutated Bcl‐2 and wild‐type Bax complexes with experimentally verified binding were identified from previous studies wherein, binding for all complexes was reportedly disrupted except one. Several protein–protein docking methods such as ClusPro, HDOCK, PatchDock, FireDock, InterEVDock2 and several mutation prediction methods such as PolyPhen‐2, SIFT, and OncoKB have been used to predict the effect of mutation to disrupt the binding between Bcl‐2 and Bax. The result obtained was compared with the known experimental data.Results: The protein–protein docking method, ClusPro, employed in the present study confirmed that the binding affinity of 11 out of 13 complexes decreases. Similarly, binding affinity computed for all the 10 wild‐type Bcl‐2 and mutated Bax complexes agreed with experimentally verified results.Conclusion: Several methods like PolyPhen‐2, SIFT, and OncoKB have been developed to predict cancer‐associated or deleterious mutations, but no method is available to predict apoptosis‐inducing mutations. Thus, in this study, we have examined the mutations in Bcl‐2 and Bax proteins that disrupt their binding, which is crucial for inducing apoptosis to eradicate cancer. This study suggests that protein–protein docking methods can play a significant role in the identification of hotspot mutations in Bcl‐2 or Bax that can disrupt their binding with wild‐type partner to induce apoptosis in cancer cells.