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CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag.
Basso-Valentina, F, Levy, G, Varghese, LN, Oufadem, M, Neven, B, Boussard, C, Balayn, N, Marty, C, Vainchenker, W, Plo, I, et al
Blood. 2021;(6):480-485
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Abstract
Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in 1 consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. Next-generation sequencing revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell-surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated with its retention in the endoplasmic reticulum. The low cell-surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm-associated calreticulin (CALR) mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant CALR mutant protein. Finally, the endogenous CALR mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.
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Etoposide combined with ruxolitinib for refractory hemophagocytic lymphohistiocytosis during pregnancy: a case report and literature review.
Wang, S, Wu, J, Jing, X, Zhang, Y, Tang, H, Wu, J
Hematology (Amsterdam, Netherlands). 2019;(1):751-756
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder caused by uncontrolled inflammatory responses and the activation of T lymphocytes. This life-threatening disease, characterized by fever, cytopenia and hepatosplenomegaly, is extremely rare during pregnancy with high mortality. Despite the improvement of treatment regimen in recent years, HLH is still a great challenge for clinicians. Here, we described a 26-year-old woman who admitted to our hospital at her first pregnancy with pyrexia. Her condition continued to deteriorate after receiving broad-spectrum antimicrobials, presenting with fever, pancytopenia, hepatosplenomegaly, ferritin ≥ 500 μg/L, hemophagocytosis and low NK-cell activity. HLH was eventually diagnosed by clinical manifestation and laboratory examination results. Then the patient recovered well after treatment with etoposide combined with ruxolitinib therapy and underwent successful induced-labor operation. Additionally, we summarized similar cases from the literature to improve the management of HLH during pregnancy. In conclusion, this study highlights the challenges and difficulties in the diagnosis and management of patients with HLH during pregnancy. Moreover, this is the first case report of etoposide combined with ruxolitinib in the treatment of patients with refractory secondary HLH during pregnancy.
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Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
Shaw, AT, Friboulet, L, Leshchiner, I, Gainor, JF, Bergqvist, S, Brooun, A, Burke, BJ, Deng, YL, Liu, W, Dardaei, L, et al
The New England journal of medicine. 2016;(1):54-61
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Abstract
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).
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Fomepizole as a therapeutic strategy in paediatric methanol poisoning. A case report and review of the literature.
De Brabander, N, Wojciechowski, M, De Decker, K, De Weerdt, A, Jorens, PG
European journal of pediatrics. 2005;(3):158-61
Abstract
UNLABELLED Methanol poisoning is not frequently observed in children; however, without treatment, serious intoxication can be complicated by visual impairment, coma, metabolic acidosis, respiratory and circulatory insufficiency and death. Treatment in a paediatric intensive care is therefore compulsory. Methanol is metabolised in the liver by alcohol dehydrogenase to the toxic metabolites formaldehyde and formic acid. Classically, ethanol is given as a competitive inhibitor in order to avoid the formation of these compounds. We report on the use of fomepizole (4-methylpyrazole),a new and potent inhibitor of alcohol dehydrogenase, in a 3-year-old boy after the intake of a toxic amount of methanol. The course was uneventful and the use of fomepizole was not accompanied by any side-effects. An overview is given of all cases of paediatric poisoning in which fomepizole was used. CONCLUSION Fomepizole seems to be a safe and valid alternative to ethanol in cases of paediatric methanol poisoning.