SUMMARY It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

Myeloproliferative neoplasms are uncommon disorders in children, for which we have limited understanding of the pathogenesis and optimal management. JAK2 and MPL mutations, while common drivers of myeloproliferative neoplasms in adult patients, are not clearly linked to pediatric disease. Management and clinical outcomes in adults have been well delineated with defined recommendations for risk stratification and treatment. This is not the case for pediatric patients, for whom there is neither a standard approach to workup nor any consensus regarding management. This review will discuss thrombocytosis in children, including causes of thrombocytosis in children, the limited knowledge we have regarding pediatric primary thrombocytosis, and our thoughts on potential risk stratification and management, and future questions to be answered by laboratory research and collaborative clinical study. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o ngenerally on control at the transcriptional level. 13 This rate depends upon TPO binding to its receptor, which in turn depends upon how many TPO-R bearing cells are accessible, as well as how many receptors they express.14 Low platelet counts will lead to decreased TPO clearance (less receptors in the circulation) and therefore increased levels of TPO; the reverse occurs with higher platelet counts, i.e. thrombocytosis. There are variations to this basic principal, for example in the setting of idiopathic thrombocytopenia (thrombocytopenia due to destruction). In these cases, the number of megakaryocytes and megakaryocyte mass may also influence TPO regulation and circulating levels. 15,16 Causes of reactive thrombocytosis in childrenSecondary, or reactive, thrombocytosis is a common occurrence in children. It has been reported to occur in 6-15% of hospitalized children, with variations based on age. Most of these children had thrombocytosis that could be characterized as mild, but others transiently reached levels over 900,000. [17][18][19][20] Causes of secondary thrombocytosis are many and varied (Table 1). Infection is the most common, including viral and bacterial pathogens, and both acute and chronic infections. Especially in children under one year of age, any infection seems capable of triggering a high platelet count. Inflammatory diseases, e.g. Kawasaki disease, rheumatoid arthritis, and inflammatory bowel disease, are commonly associated with reactive thrombocytosis, as are hypoxia, trauma, blood loss, and malignancy. 19,21,22 Iron deficiency also seems to be a frequent cause of secondary thrombocytosis. 20 It is believed that underlying mechanisms of secondary thrombocytosis can be explained by upregulation of TPO expression and resultant increased TPO levels. Hepatic TPO mRNA expression is increased with inflammation. Figure 1 shows our groups' proposed diagnostic algorithm for approaching patients with elevated platelets. Evaluation for secondary causes, such as iron deficiency or inflammatory or infectious disorders is conducted. Iron deficiency and othe...

IntroductionPolycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are classified as BCR-ABL Ϫ myeloproliferative neoplasms (MPNs), typified by clonal proliferation of 1 or more myeloid lineages. 1,2 There are approximately 130 000 to 150 000 patients with MPN in the United States, which makes these disorders among the most common hematopoietic malignancies. 3 Patients with MPN are at high risk for several disease-related complications, including bleeding, thrombosis, splenomegaly, progressive bone marrow failure, and transformation to acute myeloid leukemia (AML). Current therapies for PV and ET are largely empiric, and include antiplatelet therapy, phlebotomy, hydroxyurea, anagrelide, and IFN-␥. 4 For patients with PMF or with post-PV/ET myelofibrosis, treatment options are limited, with the notable exception of allogeneic stem cell transplantation for the subset of patients in which age and/or comorbidities do not exclude transplantation as a therapeutic option. 5,6 There is therefore a need for novel therapies for patients with these disorders.Although previous studies had demonstrated the clonal stem cell origin of these disorders, 7,8 the genetic basis of these disorders was not known until several groups reported the identification of a recurrent somatic mutation in JAK2 (JAK2V617F) in approximately 90% to 95% of patients with PV and in approximately 50% to 60% of patients with Expression of JAK2V617F in vitro transforms hematopoietic cells to cytokine-independent growth and leads to constitutive activation of downstream signaling pathways. 9,15 In addition, expression of JAK2V617F in vivo using the murine bone marrow transplantation (BMT) assay results in a short latency, fully penetrant MPN notable for marked polycythemia, hepatosplenomegaly, and variable progression to myelofibrosis. [16][17][18][19] These data demonstrate the importance of JAK2V617F to the pathogenesis of JAK2V617F-positive MPN.Although the discovery of JAK2V617F mutations in almost all patients with PV and approximately half of those with ET and PMF provided important insight into the molecular basis of these MPNs, the etiology of JAK2V617F Ϫ MPN remained unknown. Investigators subsequently identified somatic activating mutations in exon 12 of JAK2 in patients with JAK2V617F Ϫ PV; 20 however, alternate JAK2 mutations were not identified in JAK2V617F Ϫ ET and PMF. Based on the observation that the JAK2V617F kinase requires expression of a type I homodimeric cytokine receptor (EPOR, MPL, GCSFR) to efficiently transform hematopoietic cells, 15 investigators sequenced these cytokine receptors in patients with MPN and identified somatic mutations at codon 515 of the thrombopoietin receptor (MPLW515L) in ET and PMF. 21 Subsequent to the initial identification of the MPLW515L allele, additional somatic mutations at codon 515 (MPLW515K, MPLW515A) 22,23 and at codon 505 (MPLS505N) 24 21 More importantly, overexpression of MPLW515L in the murine BMT assay results in development of an acute myeloproliferative ne...

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Key Points PU-H71, a novel purine scaffold inhibitor, shows potent therapeutic efficacy in JAK-mutant ALL cells and mouse models. HSP90 inhibition retains therapeutic efficacy in ruxolitinib-persistent JAK-mutant ALL cells.