Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F-positive MPNs in vivo.

The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling through several type I cytokine receptors, namely the erythropoietin receptor, the thrombopoietin receptor (TpoR)/myeloproliferative leukemia (Mpl) protein, and the granulocyte colony-stimulating factor receptor. Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/Mpl absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, in which regulation of Jak2 expression does not depend on its natural promoter.

Structural insights into the interaction between testis-specific Y-encoded-like protein 5 and ubiquitin-specific protease 7.

The Alternative Lengthening of Telomeres (ALT) mechanism enables telomere maintenance, contributing to the immortality of certain cancer cells. Disrupting the interaction between testis-specific Y-encoded-like protein 5 (TSPYL5) and ubiquitin-specific protease 7 (USP7) has emerged as a promising strategy to target ALT-dependent cancers. While the N-terminal MATH domain of USP7 mediates the protein interaction, the regions of TSPYL5 involved in binding remain unclear.

Increased RhoA pathway activation downstream of αIIbβ3/SRC contributes to heterozygous Bernard Soulier syndrome.

Bernard Soulier syndrome (BSS) is a severe bleeding disorder with moderate to severe thrombocytopenia, giant platelets, and platelet dysfunction, caused by biallelic mutations in GP1BA, GP1BB, or GP9 genes. We generated induced pluripotent stem cells (iPSC) from a BSS patient with a novel heterozygous GP1BA p.N103D mutation, resulting in moderate macrothrombocytopenia.

LIBX-A401: A Novel Selective Inhibitor of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode.

Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a pivotal enzyme in lipid metabolism, has emerged as a therapeutic target for ferroptosis-related conditions and cancer. However, its reference inhibitor, rosiglitazone, has off-target activity on peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of lipid homeostasis. Here, the discovery of LIBX-A401, a potent ACSL4 inhibitor derived from rosiglitazone devoid of PPARγ activity, is reported.

Modulation of human thrombopoietin receptor conformations uncouples JAK2 V617F-driven activation from cytokine-induced stimulation.

The thrombopoietin receptor (TpoR) plays a central role in myeloproliferative neoplasms (MPNs). Mutations in JAK2, calreticulin, or TpoR itself drive the constitutive activation of TpoR and uncontrolled proliferation and differentiation of hematopoietic stem cells and progenitors. The JAK2 V617F mutation is responsible for most MPNs, and all driver mutants induce pathologic TpoR activation.

Constitutive activation and oncogenicity are mediated by loss of helical structure at the cytosolic boundary of thrombopoietin receptor mutant dimers.

Dimerization of the thrombopoietin receptor (TpoR) is necessary for receptor activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations of the transmembrane (TM) helices within a receptor dimer can lead to different signaling outputs. Here we addressed the structural basis of activation for receptor mutations S505N and W515K that induce myeloproliferative neoplasms.

Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology.

Aging is the main risk factor for Alzheimer's disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis.

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2 with Jak2, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2 unexpectedly delayed myelofibrosis induced by Jak2 and decreased TGFβ1 serum level.

Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation.

Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation.

Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates.

Most neurodegenerative diseases have the characteristics of protein folding disorders, i.e., they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress.

Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms.

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.

Functional Consequences of Mutations in Myeloproliferative Neoplasms.

Driver mutations occur in Janus kinase 2 (), thrombopoietin receptor (), and calreticulin () in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). From mutations leading to one amino acid substitution in JAK2 or MPL, to frameshift mutations in CALR resulting in a protein with a different C-terminus, all the mutated proteins lead to pathologic and persistent JAK2-STAT5 activation. The most prevalent mutation, JAK2 V617F, is associated with the 3 entities polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), while and mutations are associated only with ET and MF.

Erratum: Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization.

[This corrects the article DOI: 10.1016/j.isci.

Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization.

Amyloid precursor protein (APP) cleavage by the β-secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled-coil to the C99 TM domain, the dimer containing the Gly-x-x-x-Gly motif in the interface promoted the Aβ processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling.

Expression of the activation markers Blimp1, Foxp1 and pStat3 in extranodal diffuse large B-cell lymphomas.

Different studies have suggested that the expression of biomarkers related to lymphoid cell activation may provide information on the behavior of DLBCL. Most studies have concentrated on nodal or a mixture of nodal and extranodal lymphomas. The differential expression and potential clinical impact of these markers in a homogeneous group of extranodal DLBCLs are not well defined.