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1. The overlapping burden of the three leading causes of disability and death in sub-Saharan African children

Author

Reiner, R.C., Welgan, C.A., Troeger, C.E., Baumann, M.M., Weiss, D.J., Deshpande, A., Blacker, B.F., Miller-Petrie, M.K., Earl, L., Bhatt, S., Abolhassani, H., Abosetugn, A.E., Abu-Gharbieh, E., Adekanmbi, V., Adetokunboh, O.O., Aghaali, M., Aji, B., Alahdab, F., Al-Aly, Z., Alhassan, R.K., Ali, S., Alizade, H., Aljunid, S.M., Almasi-Hashiani, A., Al-Mekhlafi, H.M., Altirkawi, K.A., Alvis-Guzman, N., Amare, A.T., Amini, S., Amugsi, D.A., Ancuceanu, R., Andrei, C.L., Ansari, F., Anvari, D., Appiah, S.C.Y., Arabloo, J., Aremu, O., Atout, M.M.W., Ausloos, M., Ausloos, F., Ayanore, M.A., Aynalem, Y.A., Azene, Z.N., Badawi, A., Baig, A.A., Banach, M., Bedi, N., Bhagavathula, A.S., Bhandari, D., Bhardwaj, N., Bhardwaj, P., Bhattacharyya, K., Bhutta, Z.A., Bijani, A., Birhanu, T.T.M., Bitew, Z.W., Boloor, A., Brady, O.J., Butt, Z.A., Car, J., Carvalho, F., Casey, D.C., Chattu, V.K., Chowdhury, M.A.K., Chu, D.-., Coelho, C.H., Cook, A.J., Damiani, G., Daoud, F., Gela, J.D., Darwish, A.H., Daryani, A., Das, J.K., Davis Weaver, N., Deribe, K., Desalew, A., Dharmaratne, S.D., Dianatinasab, M., Diaz, D., Djalalinia, S., Dorostkar, F., Dubljanin, E., Duko, B., Dwyer-Lindgren, L., Effiong, A., El Sayed Zaki, M., El Tantawi, M., Enany, S., Fattahi, N., Feigin, V.L., Fernandes, E., Ferrara, P., Fischer, F., Foigt, N.A., Folayan, M.O., Foroutan, M., Frostad, J.J., Fukumoto, T., Gaidhane, A.M., Gebrekrstos, H.G.G.K., Gebremeskel, L., Gebreslassie, A.A., Gething, P.W., Gezae, K.E., Ghadiri, K., Ghashghaee, A., Golechha, M., Gubari, M.I.M., Hadgu, F.B., Hamidi, S., Handiso, D.W., Hashi, A., Hassan, S., Hayat, K., Herteliu, C., H. C., H., Holla, R., Hosseinzadeh, M., Househ, M., Hussain, R., Hwang, B.-., Ibitoye, S.E., Ilesanmi, O.S., Ilic, I.M., Ilic, M.D., Irvani, S.S.N., Jaafari, J., Javaheri, T., Jha, R.P., Johnson, K.B., Jonas, J.B., Jozwiak, J.J., Kabir, A., Kalhor, R., Kanchan, T., Karch, A., Kayode, G.A., Keiyoro, P.N., Khader, Y.S., Khalil, I.A., Khan, M.N., Khan, M., Khan, G., Khatab, K., Khater, M.M., Khatib, M.N., Kianipour, N., Kim, Y.J., Kimokoti, R.W., Kisa, S., Kisa, A., Kissoon, N., Kochhar, S., Koolivand, A., Kopec, J.A., Koyanagi, A., Krishan, K., Kumar, P., Kurmi, O.P., Kusuma, D., Lal, D.K., Lami, F.H., Landires, I., Lansingh, V.C., Lasrado, S., La Vecchia, C., Lazzar-Atwood, A., Lee, P.H., Legrand, K.E., Lewycka, S., Li, B., Lim, S.S., Lindstedt, P.A., Liu, X., Longbottom, J., Lopez, A.D., Magdy Abd El Razek, H., Mahasha, P.W., Maleki, A., Mamun, A.A., Mansournia, M.A., Marczak, L.B., Martins-Melo, F.R., Mayala, B.K., Meharie, B.G., Melese, A., Mendoza, W., Menezes, R.G., Mengesha, E.W., Mensah, G.A., Meretoja, T.J., Mestrovic, T., Miller, T.R., Mirrakhimov, E.M., Moazen, B., Mohammad Gholi Mezerji, N., Mohammadi, S., Mohammed, S., Mokdad, A.H., Moradi, M., Moradzadeh, R., Moraga, P., Mosser, J.F., Murray, C.J.L., Naderi, M., Nagarajan, A.J., Nazari, J., Ndejjo, R., Negoi, I., Ngunjiri, J.W., Nguyen, Q.A.P., Nguyen, H.L.T., Nnaji, C.A., Noubiap, J.J., Nunez-Samudio, V., Olagunju, A.T., Olusanya, J.O., Olusanya, B.O., Omer, M.O., Onwujekwe, O.E., Otstavnov, N., Otstavnov, S.S., Owolabi, M.O., P A, M., Padubidri, J.R., Pana, A., Peprah, E.K., Pham, H.Q., Pigott, D.M., Pirestani, M., Postma, M.J., Pottoo, F.H., Pourjafar, H., Quazi Syed, Z., Rahim, F., Rahimi-Movaghar, V., Rahman, M.H.U., Rao, S.J., Rao, P.C., Rathi, P., Rawaf, S., Rawaf, D.L., Rawal, L., Rawassizadeh, R., Regassa, L.D., Renzaho, A.M.N., Rezaei, N., Rezai, M.S., Ribeiro, A.I., Rickard, J., Rios-Gonzalez, C.M., Rumisha, S.F., Sabour, S., Sajadi, S.M., Salomon, J.A., Samadi Kafil, H., Samy, A.M., Sanabria, J., Sartorius, B., Saxena, D., Schaeffer, L.E., Senthilkumaran, S., Sha, F., Shaheen, A.A., Shaikh, M.A., Sharma, R., Sheikh, A., Shibuya, K., Shigematsu, M., Il Shin, J., Simonetti, B., Singh, J.A., Smith, D.L., Soheili, A., Sokhan, A., Spurlock, E.E., Sreeramareddy, C.T., Sufiyan, M.B., Swartz, S.J., Tadesse, D.B., Tamiru, A.T., Tefera, Y.G., Temsah, M.-., Tessema, Z.T., Titova, M.V., Tran, B.X., Truong, P.N., Unnikrishnan, B., Upadhyay, E., Vasankari, T.J., Vasseghian, Y., Violante, F.S., G. T., V., Waheed, Y., Wamai, R.G., Wassie, E.G., Welay, F.T., Wickramasinghe, N.D., Wiens, K.E., Wijeratne, T., Wiysonge, C.S., Wondmeneh, T.G., Yamada, T., Yaya, S., Yeshitila, Y.G., Yip, P., Yonemoto, N., Yu, C., Yuce, D., Yusefzadeh, H., Zaidi, Z., Zamanian, M., Zangeneh, A., Zhang, Z.-., Zhang, Y., Ziapour, A., Hay, S.I., Reiner, RC Jr, Welgan, CA, Troeger, CE, Baumann, MM, Duko, Bereket, Hay, Simon I, LBD Triple Collaborators, Value, Affordability and Sustainability (VALUE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Microbes in Health and Disease (MHD), Reiner, R, Welgan, C, Troeger, C, Baumann, M, Weiss, D, Deshpande, A, Blacker, B, Miller-Petrie, M, Earl, L, Bhatt, S, Abolhassani, H, Abosetugn, A, Abu-Gharbieh, E, Adekanmbi, V, Adetokunboh, O, Aghaali, M, Aji, B, Alahdab, F, Al-Aly, Z, Alhassan, R, Ali, S, Alizade, H, Aljunid, S, Almasi-Hashiani, A, Al-Mekhlafi, H, Altirkawi, K, Alvis-Guzman, N, Amare, A, Amini, S, Amugsi, D, Ancuceanu, R, Andrei, C, Ansari, F, Anvari, D, Appiah, S, Arabloo, J, Aremu, O, Atout, M, Ausloos, M, Ausloos, F, Ayanore, M, Aynalem, Y, Azene, Z, Badawi, A, Baig, A, Banach, M, Bedi, N, Bhagavathula, A, Bhandari, D, Bhardwaj, N, Bhardwaj, P, Bhattacharyya, K, Bhutta, Z, Bijani, A, Birhanu, T, Bitew, Z, Boloor, A, Brady, O, Butt, Z, Car, J, Carvalho, F, Casey, D, Chattu, V, Chowdhury, M, Chu, D, Coelho, C, Cook, A, Damiani, G, Daoud, F, Gela, J, Darwish, A, Daryani, A, Das, J, Davis Weaver, N, Deribe, K, Desalew, A, Dharmaratne, S, Dianatinasab, M, Diaz, D, Djalalinia, S, Dorostkar, F, Dubljanin, E, Duko, B, Dwyer-Lindgren, L, Effiong, A, El Sayed Zaki, M, El Tantawi, M, Enany, S, Fattahi, N, Feigin, V, Fernandes, E, Ferrara, P, Fischer, F, Foigt, N, Folayan, M, Foroutan, M, Frostad, J, Fukumoto, T, Gaidhane, A, Gebrekrstos, H, Gebremeskel, L, Gebreslassie, A, Gething, P, Gezae, K, Ghadiri, K, Ghashghaee, A, Golechha, M, Gubari, M, Hadgu, F, Hamidi, S, Handiso, D, Hashi, A, Hassan, S, Hayat, K, Herteliu, C, Ho, H, Holla, R, Hosseinzadeh, M, Househ, M, Hussain, R, Hwang, B, Ibitoye, S, Ilesanmi, O, Ilic, I, Ilic, M, Irvani, S, Jaafari, J, Javaheri, T, Jha, R, Johnson, K, Jonas, J, Jozwiak, J, Kabir, A, Kalhor, R, Kanchan, T, Karch, A, Kayode, G, Keiyoro, P, Khader, Y, Khalil, I, Khan, M, Khan, G, Khatab, K, Khater, M, Khatib, M, Kianipour, N, Kim, Y, Kimokoti, R, Kisa, S, Kisa, A, Kissoon, N, Kochhar, S, Koolivand, A, Kopec, J, Koyanagi, A, Krishan, K, Kumar, P, Kurmi, O, Kusuma, D, Lal, D, Lami, F, Landires, I, Lansingh, V, Lasrado, S, La Vecchia, C, Lazzar-Atwood, A, Lee, P, Legrand, K, Lewycka, S, Li, B, Lim, S, Lindstedt, P, Liu, X, Longbottom, J, Lopez, A, Magdy Abd El Razek, H, Mahasha, P, Maleki, A, Mamun, A, Mansournia, M, Marczak, L, Martins-Melo, F, Mayala, B, Meharie, B, Melese, A, Mendoza, W, Menezes, R, Mengesha, E, Mensah, G, Meretoja, T, Mestrovic, T, Miller, T, Mirrakhimov, E, Moazen, B, Mohammad Gholi Mezerji, N, Mohammadi, S, Mohammed, S, Mokdad, A, Moradi, M, Moradzadeh, R, Moraga, P, Mosser, J, Murray, C, Naderi, M, Nagarajan, A, Nazari, J, Ndejjo, R, Negoi, I, Ngunjiri, J, Nguyen, Q, Nguyen, H, Nnaji, C, Noubiap, J, Nunez-Samudio, V, Olagunju, A, Olusanya, J, Olusanya, B, Omer, M, Onwujekwe, O, Otstavnov, N, Otstavnov, S, Owolabi, M, P A, M, Padubidri, J, Pana, A, Peprah, E, Pham, H, Pigott, D, Pirestani, M, Postma, M, Pottoo, F, Pourjafar, H, Quazi Syed, Z, Rahim, F, Rahimi-Movaghar, V, Rahman, M, Rao, S, Rao, P, Rathi, P, Rawaf, S, Rawaf, D, Rawal, L, Rawassizadeh, R, Regassa, L, Renzaho, A, Rezaei, N, Rezai, M, Ribeiro, A, Rickard, J, Rios-Gonzalez, C, Rumisha, S, Sabour, S, Sajadi, S, Salomon, J, Samadi Kafil, H, Samy, A, Sanabria, J, Sartorius, B, Saxena, D, Schaeffer, L, Senthilkumaran, S, Sha, F, Shaheen, A, Shaikh, M, Sharma, R, Sheikh, A, Shibuya, K, Shigematsu, M, Il Shin, J, Simonetti, B, Singh, J, Smith, D, Soheili, A, Sokhan, A, Spurlock, E, Sreeramareddy, C, Sufiyan, M, Swartz, S, Tadesse, D, Tamiru, A, Tefera, Y, Temsah, M, Tessema, Z, Titova, M, Tran, B, Truong, P, Unnikrishnan, B, Upadhyay, E, Vasankari, T, Vasseghian, Y, Violante, F, Vu, G, Waheed, Y, Wamai, R, Wassie, E, Welay, F, Wickramasinghe, N, Wiens, K, Wijeratne, T, Wiysonge, C, Wondmeneh, T, Yamada, T, Yaya, S, Yeshitila, Y, Yip, P, Yonemoto, N, Yu, C, Yuce, D, Yusefzadeh, H, Zaidi, Z, Zamanian, M, Zangeneh, A, Zhang, Z, Zhang, Y, Ziapour, A, Hay, S, HUS Comprehensive Cancer Center, Institute for Molecular Medicine Finland, Clinicum, Helsinki University Hospital Area, and Department of Oncology

Subjects
Multidisciplinary, Settore MED/42 - Igiene Generale e Applicata, 3122 Cancers, malaria, General Physics and Astronomy, COVID-19, General Chemistry, 3126 Surgery, anesthesiology, intensive care, radiology, infectious diseases, Sub-Saharian Africa, General Biochemistry, Genetics and Molecular Biology, Settore MED/01 - Statistica Medica, Children mortality, epidemiology, biogeography
Abstract

Publisher Copyright: © 2022, The Author(s). Despite substantial declines since 2000, lower respiratory infections (LRIs), diarrhoeal diseases, and malaria remain among the leading causes of nonfatal and fatal disease burden for children under 5 years of age (under 5), primarily in sub-Saharan Africa (SSA). The spatial burden of each of these diseases has been estimated subnationally across SSA, yet no prior analyses have examined the pattern of their combined burden. Here we synthesise subnational estimates of the burden of LRIs, diarrhoea, and malaria in children under-5 from 2000 to 2017 for 43 sub-Saharan countries. Some units faced a relatively equal burden from each of the three diseases, while others had one or two dominant sources of unit-level burden, with no consistent pattern geographically across the entire subcontinent. Using a subnational counterfactual analysis, we show that nearly 300 million DALYs could have been averted since 2000 by raising all units to their national average. Our findings are directly relevant for decision-makers in determining which and targeting where the most appropriate interventions are for increasing child survival.

Published
2022

2. The Burden of Proof studies: assessing the evidence of risk.

Author

Zheng P, Afshin A, Biryukov S, Bisignano C, Brauer M, Bryazka D, Burkart K, Cercy KM, Cornaby L, Dai X, Dirac MA, Estep K, Fay KA, Feldman R, Ferrari AJ, Gakidou E, Gil GF, Griswold M, Hay SI, He J, Irvine CMS, Kassebaum NJ, LeGrand KE, Lescinsky H, Lim SS, Lo J, Mullany EC, Ong KL, Rao PC, Razo C, Reitsma MB, Roth GA, Santomauro DF, Sorensen RJD, Srinivasan V, Stanaway JD, Vollset SE, Vos T, Wang N, Welgan CA, Wozniak SS, Aravkin AY, and Murray CJL

Subjects
Humans, Risk Assessment methods, Risk Factors, Myocardial Ischemia, Smoking
Abstract

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses-termed the Burden of Proof studies-designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk-outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk-outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk-outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study., (© 2022. The Author(s).)

Published
2022
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3. Effects of elevated systolic blood pressure on ischemic heart disease: a Burden of Proof study.

Author

Razo C, Welgan CA, Johnson CO, McLaughlin SA, Iannucci V, Rodgers A, Wang N, LeGrand KE, Sorensen RJD, He J, Zheng P, Aravkin AY, Hay SI, Murray CJL, and Roth GA

Subjects
Antihypertensive Agents pharmacology, Antihypertensive Agents therapeutic use, Blood Pressure, Humans, Reactive Oxygen Species, Hypertension drug therapy, Myocardial Ischemia drug therapy, Myocardial Ischemia epidemiology
Abstract

High systolic blood pressure (SBP) is a major risk factor for ischemic heart disease (IHD), the leading cause of death worldwide. Using data from published observational studies and controlled trials, we estimated the mean SBP-IHD dose-response function and burden of proof risk function (BPRF), and we calculated a risk outcome score (ROS) and corresponding star rating (one to five). We found a very strong, significant harmful effect of SBP on IHD, with a mean risk-relative to that at 100 mm Hg SBP-of 1.39 (95% uncertainty interval including between-study heterogeneity 1.34-1.44) at 120 mm Hg, 1.81 (1.70-1.93) at 130 mm Hg and 4.48 (3.81-5.26) at 165 mm Hg. The conservative BPRF measure indicated that SBP exposure between 107.5 and 165.0 mm Hg raised risk by 101.36% on average, yielding a ROS of 0.70 and star rating of five. Our analysis shows that IHD risk was already increasing at 120 mm Hg SBP, rising steadily up to 165 mm Hg and increasing less steeply above that point. Our study endorses the need to prioritize and strengthen strategies for screening, to raise awareness of the need for timely diagnosis and treatment of hypertension and to increase the resources allocated for understanding primordial prevention of elevated blood pressure., (© 2022. The Author(s).)

Published
2022
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4. Oral rehydration therapies in Senegal, Mali, and Sierra Leone: a spatial analysis of changes over time and implications for policy.

Author

Wiens KE, Schaeffer LE, Sow SO, Ndoye B, Cain CJ, Baumann MM, Johnson KB, Lindstedt PA, Blacker BF, Bhutta ZA, Cormier NM, Daoud F, Earl L, Farag T, Khalil IA, Kinyoki DK, Larson HJ, LeGrand KE, Cook AJ, Malta DC, Månsson JC, Mayala BK, Mokdad AH, Ogbuanu IU, Sankoh O, Sartorius B, Topor-Madry R, Troeger CE, Welgan CA, Werdecker A, Hay SI, and Reiner RC Jr

Subjects
Administration, Oral, Bicarbonates therapeutic use, Child, Child Mortality history, Child Mortality trends, Child, Preschool, Diarrhea epidemiology, Female, Glucose therapeutic use, Health Policy history, History, 20th Century, History, 21st Century, Humans, Infant, Male, Mali epidemiology, Potassium Chloride therapeutic use, Senegal epidemiology, Severity of Illness Index, Sierra Leone epidemiology, Sodium Chloride therapeutic use, Spatial Analysis, Time Factors, Treatment Outcome, Diarrhea therapy, Fluid Therapy history, Fluid Therapy methods, Fluid Therapy statistics & numerical data, Fluid Therapy trends, Health Policy trends
Abstract

Background: Oral rehydration solution (ORS) is a simple intervention that can prevent childhood deaths from severe diarrhea and dehydration. In a previous study, we mapped the use of ORS treatment subnationally and found that ORS coverage increased over time, while the use of home-made alternatives or recommended home fluids (RHF) decreased, in many countries. These patterns were particularly striking within Senegal, Mali, and Sierra Leone. It was unclear, however, whether ORS replaced RHF in these locations or if children were left untreated, and if these patterns were associated with health policy changes., Methods: We used a Bayesian geostatistical model and data from household surveys to map the percentage of children with diarrhea that received (1) any ORS, (2) only RHF, or (3) no oral rehydration treatment between 2000 and 2018. This approach allowed examination of whether RHF was replaced with ORS before and after interventions, policies, and external events that may have impacted healthcare access., Results: We found that RHF was replaced with ORS in most Sierra Leone districts, except those most impacted by the Ebola outbreak. In addition, RHF was replaced in northern but not in southern Mali, and RHF was not replaced anywhere in Senegal. In Senegal, there was no statistical evidence that a national policy promoting ORS use was associated with increases in coverage. In Sierra Leone, ORS coverage increased following a national policy change that abolished health costs for children., Conclusions: Children in parts of Mali and Senegal have been left behind during ORS scale-up. Improved messaging on effective diarrhea treatment and/or increased ORS access such as through reducing treatment costs may be needed to prevent child deaths in these areas.

Published
2020
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5. Identifying residual hotspots and mapping lower respiratory infection morbidity and mortality in African children from 2000 to 2017.

Author

Reiner RC, Welgan CA, Casey DC, Troeger CE, Baumann MM, Nguyen QP, Swartz SJ, Blacker BF, Deshpande A, Mosser JF, Osgood-Zimmerman AE, Earl L, Marczak LB, Munro SB, Miller-Petrie MK, Rodgers Kemp G, Frostad J, Wiens KE, Lindstedt PA, Pigott DM, Dwyer-Lindgren L, Ross JM, Burstein R, Graetz N, Rao PC, Khalil IA, Davis Weaver N, Ray SE, Davis I, Farag T, Brady OJ, Kraemer MUG, Smith DL, Bhatt S, Weiss DJ, Gething PW, Kassebaum NJ, Mokdad AH, Murray CJL, and Hay SI

Subjects
Africa epidemiology, Bayes Theorem, Child, Preschool, Humans, Incidence, Infant, Infant, Newborn, Prevalence, Public Health standards, Risk Factors, Morbidity, Respiratory Tract Infections mortality
Abstract

Lower respiratory infections (LRIs) are the leading cause of death in children under the age of 5, despite the existence of vaccines against many of their aetiologies. Furthermore, more than half of these deaths occur in Africa. Geospatial models can provide highly detailed estimates of trends subnationally, at the level where implementation of health policies has the greatest impact. We used Bayesian geostatistical modelling to estimate LRI incidence, prevalence and mortality in children under 5 subnationally in Africa for 2000-2017, using surveys covering 1.46 million children and 9,215,000 cases of LRI. Our model reveals large within-country variation in both health burden and its change over time. While reductions in childhood morbidity and mortality due to LRI were estimated for almost every country, we expose a cluster of residual high risk across seven countries, which averages 5.5 LRI deaths per 1,000 children per year. The preventable nature of the vast majority of LRI deaths mandates focused health system efforts in specific locations with the highest burden.

Published
2019
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6. Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism.

Author

Garbati MR, Welgan CA, Landefeld SH, Newell LF, Agarwal A, Dunlap JB, Chourasia TK, Lee H, Elferich J, Traer E, Rattray R, Cascio MJ, Press RD, Bagby GC, Tyner JW, Druker BJ, and Dao KH

Subjects
Blotting, Western, Bone Marrow metabolism, Calcium metabolism, Calreticulin metabolism, Cell Culture Techniques, Cell Nucleus metabolism, Culture Media, Conditioned, Cytokines biosynthesis, Extracellular Space metabolism, HEK293 Cells, HeLa Cells, Humans, Immunohistochemistry, Janus Kinase 2 genetics, Monocytes physiology, Primary Myelofibrosis genetics, Primary Myelofibrosis immunology, Protein Binding, Real-Time Polymerase Chain Reaction, Thrombocythemia, Essential genetics, Thrombocythemia, Essential immunology, Calreticulin genetics, Frameshift Mutation, Monocytes metabolism, Paracrine Communication genetics
Abstract

Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium-binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL-3-independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2-V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll-like receptor agonist. These effects are not dependent on the novel C-terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis., (© 2015 Wiley Periodicals, Inc.)

Published
2016
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