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Mutations in AMBRA1 aggravate β-thalassemia; targeting MYD88 mutations in lymphomas; air pollution and incident VTE risk
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Welcome to the March 6, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. First on today's podcast, a potential new therapeutic target in beta thalassemia, the E3 ubiquitin ligase AMBRA1 promotes autophagic clearance of free alpha globin. Researchers describe mutations in the AMBRA1 gene that impair this clearance, exacerbating ineffective erythropoiesis and disease severity after that targeting MYD88 mutations Blasalicid A is a compound that selectively binds to the MYD88L265Pmutant protein, which is found in a range of B cell lymphomas. New research shows its potential to inhibit tumor growth, overcome ibrutinib resistance and synergize with venetoclax. Finally, air pollution is linked to an increased risk of venous thromboembolism in a prospective community based cohort study. The findings highlight the harms of pollution and support the case for global efforts to improve public health. Our first article is mutations in AMBRA1 aggravate beta thalassemia by impairing autophagy mediated clearance of free alpha globin and the first author is Yong Long of Southern Medical University in Guangdong, China. To better understand the work of Long and co authors, it's helpful to review some pathophysiology. Beta thalassemia is caused by mutations in the HBB gene which encodes the beta globin protein. These HBB mutations reduce the synthesis of beta globin and that results in a surplus of free alpha globin chains relative to beta globin. The the excess alpha globin chains form toxic aggregates in red blood cell precursors. This results in ineffective erythropoiesis and premature hemolysis of red blood cells. Another key concept to consider is the role of autophagy in beta thalassemia. This cellular recycling process helps clear the toxic buildup of free alpha globin. The free alpha globin is sequestered in cytosolic vesicles and that cargo is delivered to lysosomes for degradation. As such, it's thought that autophagy is one factor that modulates the severity of beta thalassemia, but proof of this has been elusive. Some clues have surfaced in studies looking at a gene called ULK1. This is a gene that activates autophagy in a mouse model of beta thalassemia disrupting ulk1 led to an accumulation of free alpha globin and exacerbated hallmarks of the disease. Conversely, activating ULK1 increased free alpha globin clearance and reduced beta thalassemia related pathology. This brings us to the present article by Long and co authors. They take the research a step further, exploring the relationship between mutations in genes that regulate autophagy and disease severity. The authors studied a cohort of 1,022 patients with beta thalassemia, conducting a comprehensive analysis of 30 different genes related to autophagy and the goal was to pinpoint naturally occurring genetic variants that influence disease severity. One gene in particular stood out in this analysis, the autophagy and beclin 1 regulator 1 gene or AMBRA1. Long et al identified four rare missense mutations in AMBRA1 that were associated with worsened disease severity in these patients. In a univariate analysis, there was a significant correlation between presence of amber1 mutations and exacerbation of beta thalassemia as characterized by lower red blood cell count, decreased hematocrit and increased splenomegaly. Follow up studies focus on Ambry 1 were conducted in beta thalassemic mice, human erythroid cells and patient derived CD34 positive hematopoietic stem and progenitor cells. Collectively, these Investigations showed that Amber1 facilitated autophagy in these murine erythroid cells, increasing clearance of free alpha globin and reducing disease severity and conversely disrupting amber 1 reduced alpha globin clearance and exacerbated the disease phenotype. In functional studies, Long et al. Showed that the amber1 missense mutants destabilized ulk1, the autophagy regulating protein mentioned earlier. Furthermore, amber1 mutations inhibited LC3 lipidation, which is a key step in the initiation of autophagy. Finally, the amber1 mutations were associated with erythrotoxic effects in vitro. The mutations led to increases in intracellular levels of reactive oxygen species, higher rates of apoptosis and impairment in differentiation and maturation. Based on these findings, Long and co Authors say that amber 1 mutations aggravate beta thalassemia. They do so by impairing autophagy, reducing the clearance of free alpha globin and the results highlight the potential role for the amber1 gene as a diagnostic and therapeutic target in inherited disorders of red blood cells. Also in blood is a commentary by Christophe Lekov of Sanofi and Mitchell J. Weis of St. Jude Children' Hospital. According to Lakov and Weiss, Amber1 performs a balancing act so to speak in beta thalassemia. Amber1 adds to the repertoire of known genetic modifiers that influence the severity of beta thalassemia. And they say the current study provides the strongest evidence to date that autophagy of free alpha globin reduces the severity of human beta thalassemia. That makes beta thalassemia similar to other protein aggregation disorders, meaning that quality control mechanisms are in place to eliminate toxic aggregates and protect cells. The work also strengthens the hypothesis that beta thalassemia could be treated with drugs that enhance autophagy. And new treatments for beta thalassemia will be important in the immediate future, particularly for patients without access to curative therapies like gene therapy or allogeneic transplant. However, the success of this study spawns a number of new research questions. For example, the present study was conducted in a cohort of beta thalassemia patients from southern China. It's possible that study of other distinct populations could identify other proteins and pathways that participate in the clearance of free alpha globin. And a deeper dive is needed on how AMBER1 mutations impair autophagy as the AMBRA1 protein regulates autophagy in concert with other proteins. Finally, further investigation into the alpha globin autophagy pathway could provide insights beyond beta thalassemia. Broadly speaking, they conclude, investigating Ambrowan and ULK1 mediated mechanisms of autophagy could shed light on numerous age related disorders including neurodegeneration and cancer. Let's turn to our next research article. The first author is Wei Li of Central South University in Hunan, China and the work is entitled Lesalosid A selectively induces the degradation of MYD88 in lymphomas harboring the MYD88L265Pmutation. Let's break down that title. MYD88 stands for Myeloid Differentiation Primary Response 88. This is a widely expressed cytoplasmic adapter protein and it plays a key role in immune responses via the toll like receptor and interleukin 1 receptor signaling pathways. Li and co authors are focused on a somatic mutation resulting in a leucine to proline change at position 265 of the protein. So, putting it together we have MyD88L265P, one of the most prevalent oncogenic mutations found in hemologic malignancies. The MYD88L265P is found across a range of B cell lymphomas. The prevalence is approximately 90% in Waldenstrom macroglobinulinemia and about 25% in activated diffuse large B cell lymphoma and about 70% in primary central nervous system. There has been considerable interest in peptides and small molecule inhibitors of MYD88 as treatment for a variety of inflammatory diseases and cancers, but most of these work by disrupting MYD88 homo oligomerization mediated by the Toll I receptor domain. Others work by disrupting the binding of MYD88 to IRAC or Interleukin 1 receptor associated kinase. Still others work by modulating gene expression and altering levels of Microrna. However, none of These recently developed MYD88 inhibitors directly target L265P. The L265Pmutation results in conformational changes in the MYD88 protein. These changes affect the formation of unique complexes with other proteins and impact protein stability. The authors suggested that this has created opportunities for new therapeutic strategies based on protein degradation. With this opportunity in mind, Li et al. Searched for compounds that specifically targeted the MYD88L265Pmutant protein by employing high throughput chemical and genetic screening. They identified lesalosid A as a small molecule candidate against lymphomas expressing MYD88L265P. In their findings as published in blood, Li et al. Show that lesalosid A selectively binds to the MYD88L265 protein but had little effect on the wild type MYD88. The small molecule also enhanced the interaction between the mutant protein and the E3 ligase RNF5 in cells harboring the MyD88L265Pmutation. This interaction resulted in increased degradation of MyD88 through the ubiquitin dependent proteosomal pathway. Furthermore, lesalosid A potently inhibited the viability of lymphoma cells expressing MYD88L265P in xenograft mouse models. Lesalosid A had strong antitumor efficacy treatment induced disease remission in ibrutinib resistant lymphomas. In addition, lesalosid A had synergistic activity when combined with the BCl2 inhibitor venetoclax. According to authors, these findings highlight the potential of inducing MYD88L265P degradation using small molecules such as lasalicid A, and this could translate into promising strategies for treating lymphomas that harbor the MYD88L265Pmutation. In agreement are Joost sp, Vermat and Ruben Al Degron, authors of a commentary on the findings, Vermont and De Gron are both from Leiden University Medical center in the Netherlands. They describe LesalisID A as a promising targeted therapy for MyD88L265Pmutant DLBCL, particularly for the high risk activated B cell subtype. Typically, DLBCL is treated with a combination of CD20 targeted antibodies such as rituximab and chemotherapy, which leads to complete remission in most cases. However, this combination can cause adverse events, including myelosuppression, which increases the risk for infections. So a therapy that selectively targets tumor B cells rather than healthy B cells would be highly advantageous, Vermont and degron write in their blood commentary. Furthermore, patients with primary central nervous system lymphoma have a poor prognosis and a high prevalence of MYD88L265Pmutations, so LA A could be a promising therapeutic strategy in this setting, provided it can cross the blood brain barrier. Lesalicid A treatment may merit investigation in settings such as Waldenstrom macroglobinulinemia, especially since ibrutinib refractoriness is a key factor in mortality for these patients. Finally, the authors describe the synergistic effect of Lisalicid A with venetoclax as noteworthy. Adding Lisalicid A to venetoclax based combination regimens could enhance treatment efficacy, they say, though the potential toxicity and impact on survival would need to be quantified. Moving on to our final article, it's titled Air pollution is associated with increased risk of venous thromboembolism, or VT El the Multiethnic Study of Atherosclerosis, or mesa. The first author is Pamela L. Lotze of the School of Public Health at the University of Minnesota. Lutze and co authors focused their report on air pollution, a ubiquitous health hazard that's been linked to an elevated risk of cardiovascular disease. Concerns have also been raised regarding VT El and chronic exposure to air pollution. VT El is a large public health problem affecting approximately 1 million Americans, so even associations of modest magnitude could be important. Exposure to air pollution is widespread, so the population attributable risk may be large. In the VT El context, it's relevant that several prior studies have linked air pollution solution to markers of inflammation or coagulation. Increased exposure to nitrogen oxides was associated with a 7% higher level of D dimer. In addition, higher levels of exposure to fine particulate matter were associated with greater concentrations of C reactive protein fibrinogen and E selectin and higher concentrations of coarse particulate matter and gaseous pollutants, including carbon monoxide and nitrogen dioxide. Beyond these data, several previous studies have examined broad associations between air pollution and VTE. Some of the studies have found exposure to air pollutants to be harmful, but others have reported no significant association. Overall, the data are sparse, and most studies were conducted outside the United States. The prospective MESA study now reported in blood represents a major opportunity to advance our knowledge of this critically important topic. The MESA study involved a cohort of more than 6,500 participants recruited from 2000 to 2002 at six sites in different regions of the United States, followed for up to 18.5 years. In Mesa, air pollutants were measured every two weeks and assessed using a spatiotemporal model that incorporated cohort specific modeling. Using this unique dataset, Lutze and colleagues were able to test the hypotheses that greater exposure to pollutants are associated with increased risk of VTE. Specifically, the investigators measured levels of fine particulate matter, oxides of nitrogen, nitrogen dioxide, and ozone incident. VT EL was identified using hospital discharge records, and investigators controlled for relevant baseline characteristics, including body mass index, smoking status, and physical activity. The bottom line is that higher chronic exposure to air pollution was associated with higher risk of developing VTE. A total of 248 VTE events occurred over a median follow up of 16.7 years. Hazard ratios for VT EL incidents are reported based on pre specified increments in pollutant levels. For example, an increase of 3.6 micrograms per cubic meter in fine particulate matter was associated with a hazard ratio of 1.39, and the 95% confidence interval was 1.04 to 1.86. For nitrogen dioxide, an increase of 13.3 parts per billion was linked to a hazard ratio of 2.74 with a confidence interval of 1.57 to 4.77, and for nitrogen oxides, an increase of 30 parts per billion corresponded to a hazard ratio of 2.21. The confidence interval here was 1.42 to 3.44. The outlier was ozone. Lutzy et al. Found no significant association between ozone and risk of VT El. Based on these findings, the authors concluded that in areas with chronic exposure to ambient air pollution, rates of VT EL may be modestly higher. The findings add to accumulating evidence that air pollution exposure has adverse health effects, and they make the case for global efforts to reduce pollution. Such efforts could help ameliorate pollution related adverse health outcomes, including VT EL risk Also in Blood is a commentary on these findings. It's authored by Ingrid Pabinger and Sihan Ay of the Medical University of Vienna in Austria. They write that while the visible smog of air pollution is concerning, its hidden dangers to human health are even more alarming. This includes millions of air pollution related deaths worldwide and associations with a broad range of diseases including ischemic heart disease, stroke, lung cancer, asthma and chronic obstructive pulmonary disease. And now La T et al. Have shown that air pollution is associated with an increased risk of VT El, highlighting yet another health effect of polluted air. The study by Lutzy et al. Has limitations. Only hospitalized VT El cases were counted as outcome events and the report broadly covers VT El rather than distinguishing between pulmonary embolism and deep vein thrombosis. Nevertheless, the commentary authors say this study delivers reliable and valuable data on the association between long term air pollution and incident VT El. This could help to raise awareness and emphasize the importance of improving air quality. The authors conclude that a holistic approach incorporating renewable energy, mass transit, green spaces and reduced urbanization could help mitigate air pollution and potentially lower the risk of VTE. You have been listening to the Blood Podcast. The articles mentioned in this podcast can be found@bloodjournal.org and are linked in the show notes of this episode. Be sure to join us next week for another episode. Thank you for listening.