“…Overall, our results are in agreement with CALR mutants activating the JAK-STAT pathway with signatures that overlap, 44 but are not identical with those of JAK2V617F. 45 In conclusion, this work demonstrates that CALR mutants specifically activate TpoR in a Tpo-independent manner and bring forward a new and unexpected oncogenic mechanism: cytokine receptor activation by a mutated chaperone. For personal use only.…”
Key Points
Calreticulin mutants responsible for myeloproliferative neoplasms specifically activate the thrombopoietin receptor and in turn JAK2. Activation of the thrombopoietin receptor requires the glycan binding site and a novel C-terminal tail of the mutant calreticulin.
“…Overall, our results are in agreement with CALR mutants activating the JAK-STAT pathway with signatures that overlap, 44 but are not identical with those of JAK2V617F. 45 In conclusion, this work demonstrates that CALR mutants specifically activate TpoR in a Tpo-independent manner and bring forward a new and unexpected oncogenic mechanism: cytokine receptor activation by a mutated chaperone. For personal use only.…”
Key Points
Calreticulin mutants responsible for myeloproliferative neoplasms specifically activate the thrombopoietin receptor and in turn JAK2. Activation of the thrombopoietin receptor requires the glycan binding site and a novel C-terminal tail of the mutant calreticulin.
“…No p53 targets were detected in the marker genes of the other five clusters in Figure 1C (see Table S1). Figure 2Age-Specific Cluster Carries Signature of Pro-proliferative and Anti-proliferative Stimuli(A) Manual annotation of top 20 marker genes with Ras senescence (RIS), apoptosis (Kirschner et al., 2015), and pStat3 and pStat5 datasets (Lau et al., 2015). Red indicates p53, and green indicates pStat targets.(B) KEGG pathway analysis of marker genes for old-specific cluster.…”
SummaryAging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced stem cell function, the molecular basis of which is largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation of old HSCs carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. To investigate the relationship between JAK/STAT and p53 signaling, we challenged HSCs with a constitutively active form of JAK2 (V617F) and observed an expansion of the p53-positive subpopulation in old mice. Our results reveal cellular heterogeneity in the onset of HSC aging and implicate a role for JAK2V617F-driven proliferation in the p53-mediated functional decline of old HSCs.
“…In support of this, ectopic expression of mutant CALR in interleukin-3 (IL3)-dependent murine Ba/F3 cells conferred (MPL)-dependent increased JAK/STAT phosphorylation together with cytokine-independent growth, 13 and expression profiling of granulocytes from patients with JAK2 -mutant or CALR -mutant MPNs suggested many similarities. 14 However, analysis of direct STAT targets from primary megakaryocytes revealed substantial differences in STAT signalling downstream of JAK2 and CALR mutations, 15 and CALR-mutant MARIMO cells lack active JAK–STAT signalling and are unresponsive to JAK2 inhibitors. 16 …”
Most myeloproliferative neoplasm (MPN) patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify kinases important for survival of CALR-mutant cells, we developed a novel strategy (KISMET) that utilizes the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional small-interfering RNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the mitogen activated protein kinase (MAPK) pathway as required for growth of the CALR-mutated MARIMO cells. Expression of mutant CALR in murine or human haematopoietic cell lines was accompanied by myeloproliferative leukemia protein (MPL)-dependent activation of MAPK signalling, and MPN patients with CALR mutations showed increased MAPK activity in CD34 cells, platelets and megakaryocytes. Although CALR mutations resulted in protein instability and proteosomal degradation, mutant CALR was able to enhance megakaryopoiesis and pro-platelet production from human CD34+ progenitors. These data link aberrant MAPK activation to the MPN phenotype and identify it as a potential therapeutic target in CALR-mutant positive MPNs.
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