The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML

Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.

show abstract

“…These experiments were performed similar as described earlier (24,25). Details are provided in the SI.…”

Section: Leukemia Model With Engineered Primary Mouse Hematopoietic Smentioning

confidence: 99%

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The cyclin-dependent kinases (CDK) CDK6 and Src family kinases (SFKs) inhibit expression of EGR1 (81,82). On the contrary, Llgl1 (lethal giant larvae homolog 1) and PMA (Phorbol 12-myristate 13-acetate) contribute to the differentiation of hematopoietic stem cells (83,84). Andra Schaefer et al found that the expression of EGR-1 had a regulatory role in Epo signal transduction in leukemia cells (85).…”

Section: Pathogenesis Mechanism Of Aml By Egr1mentioning

confidence: 99%

The progress of early growth response factor 1 and leukemia

Tian

Han

Jiang

et al. 2016

IRDR

View full text Add to dashboard Cite

“…Llgl1 null mice develop severe brain dysplasia and die at birth from extensive hydrocephalus (Klezovitch et al 2004). In addition, Lgl1 null mice show defects in the development of the retina (Clark et al 2012), and loss of Llgl1 enhances hematopoietic cell numbers and activity (Heidel et al 2013). In contrast to zebrafish, Llgl2 null mice are viable and show no gross phenotypes, albeit Llgl2 appears to be necessary for branching morphogenesis during placental development (Sripathy et al 2011).…”

Section: Mus Musculusmentioning

confidence: 99%

“…Many studies have shown, using knockdown approaches, that Scribble and Dlg play key roles in the response of T and B cells to antigen presentation Round et al 2005Round et al , 2007Humphries et al 2012;Ludford-Menting et al 2005;Xavier et al 2004). However, gene knockout studies have shown minimal and/or transient effects of deletion of Scribble, Lgl1, and Dlg1 on hematopoiesis and immune cell function Hawkins et al 2013Hawkins et al , 2014Humphries et al 2012;Heidel et al 2013). The discrepancy between knockdown and knockout studies is thought to reflect compensatory mechanisms by which lymphocytes might adjust to deletion of the Scribble module genes over time (Humphries et al 2012;Pham et al 2014), and further studies are required to resolve this discrepancy.…”

Section: The Immune Synapsementioning

confidence: 99%