PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Unlabelled: Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival.

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown.

Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions.

Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O )-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments.

Author Correction: Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An online tumor board with international neurosurgical collaboration guides surgical decision-making in Western Kenya.

Telecollaboration via web-based platforms has emerged as a tool to relieve constraints on the establishment of tumor boards for neurosurgical oncology. Challenging tumor cases arising in low- and middle-income countries may benefit from the use of such models. The case of a 5-year-old boy presenting in Western Kenya with a challenging tumor and symptomatic hydrocephalus was presented on a novel web platform to a multi-national audience of neurosurgeons.

Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications.

Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O compartments, such as bone marrow (BM) niches, are well-recognized hosts of drug-resistant leukaemic cells, standard in vitro studies are routinely performed under supra-physiologic (21% O , ambient air) conditions, which limits clinical translatability.

Consecutive epigenetically-active agent combinations act in and pathways for AML.

Co-occurrence of and mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including and by hyperexpression of encoding Wnt agonist. These affect over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention.

Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-β.

Expression of DAPK1, a critical regulator of autophagy and apoptosis, is lost in a wide variety of tumors, although the mechanisms are unclear. A transcription factor complex consisting of ATF6 (an endoplasmic reticulum-resident factor) and C/EBP-β is required for the IFN-γ-induced expression of DAPK1 IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β are obligatory for the formation of this transcriptional complex. We report that defects in this pathway fail to control growth of chronic lymphocytic leukemia (CLL).

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis.

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis.

Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner.

The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease.

Granuloma annulare arising in association with pulmonary coccidioidomycosis.

Granuloma annulare (GA) is a reactive process in the dermis, related to degeneration of collagen. It may occur as an idiopathic phenomenon or in conjunction with a myriad of systemic conditions, including infectious disease. We report an interesting case of GA precipitated by pulmonary coccidioidomycosis.

Angiogram-negative subarachnoid hemorrhage: outcomes data and review of the literature.

Spontaneous subarachnoid hemorrhage (SAH) is most commonly caused by rupture of a saccular aneurysm or other structural pathologies. Occasionally, no structural cause for the hemorrhage can be identified by radiographic imaging. These hemorrhages, termed angiogram-negative SAH, are generally considered to have a better prognosis than aneurysmal SAH.

Combined open decompressive laminectomy and vertebroplasty for treatment of thoracolumbar fractures retrospective review of 41 cases.

Background: Vertebral compression fractures are common, and can occur concomitantly in patients with symptomatic degenerative stenosis. Less commonly, complicated vertebral body fractures may involve retropulsion of bone into the spinal canal, resulting in stenosis with myelopathy and/or radiculopathy. Decompression of the neural elements can lead to destabilization and progressive kyphotic deformity.

Novel combination treatments targeting chronic myeloid leukemia stem cells.

Chronic myeloid leukemia (CML) is currently considered incurable in most patients. Stem cell transplantation, an accepted curative option for which extensive experience has been gained, is limited by high morbidity and mortality rates, particularly in older patients. Tyrosine kinase inhibitors targeting BCR-ABL are widely used and induce remission in a high proportion of patients, but resistance and incomplete response to these agents portends eventual relapse and disease progression.

A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia.

Purpose: Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis.

Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL.

We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice.

Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3.

Internal tandem duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and overexpression of Survivin are frequently found in patients with acute myeloid leukemia (AML). We investigated whether Survivin mediates the enhanced survival of primary hematopoietic progenitor cells (HPCs) resulting from ITD-Flt3 signaling. Ectopic ITD-Flt3 mutants increased Survivin expression in Ba/F3 cells downstream of PI3-kinase/Akt.

Antimyeloma effects of a sesquiterpene lactone parthenolide.

Purpose: Nuclear factor-kappaB (NF-kappaB), activated in multiple myeloma (MM) cells by microenvironmental cues, confers resistance to apoptosis. The sesquiterpene lactone parthenolide targets NF-kappaB. However, its therapeutic potential in MM is not known.

Threaded interbody fusion cage for adjacent segment degenerative disease after previous anterior cervical fusion.

Background: Anterior discectomy and fusion have been used for over 50 years in the treatment of degenerative disease of the cervical spine. However, as these procedures become more common, the long-term consequences are becoming more evident. One such consequence is degeneration of an adjacent segment, which can occur in up to 17% of patients undergoing cervical fusion.