RESUMEN
Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth. We further show that the threshold of positive charge in the mutant CALR C terminus influences both binding of mutant CALR to MPL and activation of MPL signaling. We find that mutant CALR binds to the extracellular domain of MPL and that 3 tyrosine residues within the intracellular domain of MPL are required to activate signaling. With respect to mutant CALR function, we show that its lectin-dependent function is required for binding to MPL and for cytokine independent growth, whereas its chaperone and polypeptide-binding functionalities are dispensable. Together, our findings provide additional insights into the mechanism of the pathogenic mutant CALR-MPL interaction in myeloproliferative neoplasms.
Asunto(s)
Calreticulina/genética , Calreticulina/metabolismo , Trastornos Mieloproliferativos/genética , Dominios y Motivos de Interacción de Proteínas , Receptores de Trombopoyetina/genética , Receptores de Trombopoyetina/metabolismo , Calreticulina/química , Células Cultivadas , Células HEK293 , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Mutagénesis , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas , Receptores de Trombopoyetina/química , Transducción de SeñalRESUMEN
OBJECTIVES: Training in cardiothoracic surgery coincides with a time when many plan their families. Many choose to delay childbearing until the end of training, 33% of women and 20% of men reported using assisted reproductive technology (ART). States have varying laws regarding abortion and ART, which can influence these decisions. Our purpose was to elucidate the intersection of such laws and the training positions available in cardiothoracic surgery. METHODS: We identified abortion laws, abortion laws regarding insurance coverage, personhood laws that potentially influence ART, and insurance coverage of ART using publicly available data. We created choropleth maps with cardiothoracic surgery training positions identified using the National Resident Matching Program Match data for 2024. RESULTS: We found that 29.4% of cardiothoracic surgery programs (47 out of 160) are situated in states with abortion restrictions. Of 48 integrated training positions, 10 are in states with abortion restrictions. Similarly, 32 of 95 traditional thoracic positions and 5 of 17 congenital positions are in states abortion restrictions. A total of 25.6% of cardiothoracic training programs reside in states that grant personhood before birth, potentially affecting ART. Insurance coverage for abortion and ART are variable. CONCLUSIONS: Valuing reproductive rights like access to abortion, insurance coverage, and ART can potentially influence training opportunities in cardiothoracic surgery.
RESUMEN
UNLABELLED: Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN. SIGNIFICANCE: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL.