Journal of Blood & Lymph

Transmembrane-4 L-Six Family Member-1 (TM4SF1) is a small cell surface glycoprotein that is highly and selectively expressed on endothelial cells and mesenchymal stem cells. TM4SF1 regulates cellular functions by forming protein complexes called TMED (TM4SF1-enriched micro domains) that internalize via microtubules from the cell surface and transport recruited proteins to intracellular locations including the nucleus. Through a genetically manipulated mouse model, we demonstrate here that TM4SF1 is essential for blood vessel development. Tm4sf1 null embryos fail to develop blood vessels and experience lethality at E9.5. Tm4sf1 heterozygous embryos are smaller in body size during early embryonic development, and almost half die in utero due to intracranial hemorrhage in the intraventricular and subarachnoid space which becomes apparent by E17.5. Surviving Tm4sf1 heterozygotes do not display overt phenotypic differences relative to wild type littermates postnatally. Together these studies demonstrate that TM4SF1, through its molecular facilitator role in TMED, intimately regulates blood vessel formation during embryonic development.

Acute Lymphoblastic Leukemia (ALL) is the most prevalent malignancy among children. The primary therapeutic modality involves the administration of induction chemotherapy alone or in combination with diverse curative strategies. Existing evidence suggests that epigenetic mechanisms may serve as mediators of the influence of inherited genetic variations on phenotypic characteristics. Consequently, our investigation aimed to ascertain the potential role of DNA methylation in mediating the impact of genetic risk loci on childhood ALL. In mammals, the JAK/STAT pathway represents the principal signaling mechanism for a wide array of cytokines and growth factors. Activation of JAK induces cell proliferation, migration, differentiation, and apoptosis. A multitude of therapeutic interventions have been devised to modulate this signaling pathway, exhibiting varying degrees of efficacy and shortcomings. Pioneeringly, this study sheds light on the methylation status of JAK2 and STAT3, as well as the mRNA expression profiles, in ALL patients both prior to and following administration of the drug. We examined to determine whether there were any alterations in methylation and gene expression between the two genes during chemotherapy treatment.

This study, which took place from 2015 to 2017, utilized a case-control design. It included 50 blood samples from individuals recently diagnosed with Acute Lymphoblastic Leukemia (ALL) who had not yet received any chemotherapy drugs. After a two-month period of receiving the drug, these samples were retested. The study population consisted of 23 males and 27 females with a mean age of 7.52 ± 4.13. Additionally, 50 blood samples from healthy volunteers without any significant medical conditions were included in the study. This control group also consisted of 23 males and 27 females, with a mean age of 12.36 ± 5.63. All samples were stored at a temperature of -80°C until molecular analysis could be conducted. The methylation frequency of the JAK2 gene was found to be 35 (70%) in the blood sample taken from the newly diagnosed patient (referred to as sample1), 18 (36%) in the blood sample taken after the patient received chemotherapy (referred to as sample 2), and 3 (6%) in the blood samples from the healthy controls. The STAT3 gene exhibited a methylation rate of 54% (N=27) in sample1, 32% (N=16) in sample 2, and 4% (N=2) in the control group. A comparison between methylated and unmethylated samples indicated a significant disparity between the cases and controls in terms of JAK2 (OR1=36.55; 95%CI: 9.81 to 136.10, P < 0.0001) and STAT3 (OR1=28.17; 95% CI: 6.16 to 128.80, P<0.0001). Additionally, a notable distinction was observed between patients who underwent chemotherapy and the healthy individuals in relation to JAK2 (OR2=8.81; 95%CI: 2.39 to 32.40, P=0.0011) and STAT3 (OR2=11.29; 95%CI: 2.43 to 52.38, P=0.0020). In alternative terms, when we assessed the methylation status in patients subsequent to the administration of a chemotherapy drug in relation to their pre-treatment condition, a statistically significant finding was observed in JAK2 (OR3=4.14; 95%CI: 1.79 to 9.57, P=0.0009). However, no disparities were identified in STAT3 (OR3=2.49; 95%CI: 1.10 to 5). Within the framework of this investigation, we examined the disparity between the methylation of promoter DNA and the expression of genes within this pathway among patients who received the drug on the initial day, as well as the disparities with the control group. Chemotherapy drugs impeded the cell cycle and mitigated the adverse effects, particularly in the context of bone marrow metastasis, which was reliant on patient relapse in subsequent years.

Background: Patients with multiple myeloma are being seen at an increasing frequency in different indigenous African population. However, local data regarding the demographic profile, clinical characteristics, risk stratification, and treatment outcome of these patients is lacking. This study was designed to fill this existing gap in our setup. Hence, it will aid in the revision of treatment guidelines based on local data on the efficacy of existing treatment regimens and risk stratification of patients with a newly diagnosed multiple myeloma.

Methods: A single centered Hospital-based retrospective Cohort study was conducted from January 2015 to December 2019. Eighty patients with newly diagnosed MM who received non-proteasome inhibitor-based therapy at TASH, Addis Ababa, Ethiopia were analyzed in the study.

Results: Out of the 80 patients in this cohort, 51(63.8%) of the patients were males (M: F ratio 1.76:1) and the median age at diagnosis was 52 years. The commonest complications identified were anemia (56.3%) and pathologic fracture (55%). The commonest comorbid conditions were; systemic hypertension (24%), CKD (6.3%), and diabetes (5%). The median Progression-Free Survival (PFS) and Overall Survival (OS) of patients were found to be 17.5 and 20 months respectively. This study also identified factors like advanced DS stage, presence of plasmacytoma, renal dysfunction, elevated serum LDH, high levels of serum protein, and monoclonal M-protein to have adverse implication on the OS and PFS of patients.

Conclusion: Multiple Myeloma is more common in the male population group and our patients are younger than the western population. Myeloma treatment regimens like CP and CPT are found to be less effective in our patients than in patients elsewhere. This is likely to be due to the advanced stage at presentation. In resource-limited setups, where determination of cytogenetic features of myeloma is difficult, different clinical and laboratory parameters can still serve as prognostic markers of treatment outcome and patient survival.