Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I-induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma.
SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.
Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.<i></i>.
Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset.
These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia.
Granulocyte-colony stimulating factor receptor (G-CSFR) mutations have been implicated in the progression of severe congenital neutropenia (SCN) to leukemia.
Mutations in the CSF3 granulocyte colony-stimulating factor receptorCSF3R have recently been found in a large percentage of patients with chronic neutrophilic leukemia and, more rarely, in other types of leukemia.
The detection of both RUNX1 and CSF3R mutations could be used as a marker for identifying CN patients with a high risk of progressing to leukemia or MDS.
The G-CSFR has also been implicated in the etiology of disease, with mutations/variants of G-CSFR implicated in neutropenia, myelodysplasia and leukemia.
Point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptorCSF3R have been implicated in the progression of severe congenital neutropenia (CN) to leukemia.
Congenital neutropenia patients with acquired granulocyte colony-stimulating factor receptor mutations define a group with high risk for development of leukemia.
Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.
Because SCN patients with a mutation in the G-CSF receptor frequently develop leukemia, this 3-base pair deletion in the juxtamembrane sequence of the G-CSF receptor gene in this patient may be one step in the course of leukemic transformation.
Acute myeloid/NK precursor cell leukemia with trisomy 4 and a novel point mutation in the extracellular domain of the G-CSF receptor in a patient with chronic idiopathic neutropenia.
Time course of increasing numbers of mutations in the granulocyte colony-stimulating factor receptor gene in a patient with congenital neutropenia who developed leukemia.