Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia

Abstract

Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia.

Increased expression of the differentiation-defective granulocyte colony-stimulating factor receptor mRNA isoform in acute myelogenous leukemia

“…Taking into account the fact that immature myeloid cells express fewer G-CSFR molecules at their surface, it is possible that a critical threshold of signaling for initiation of the G-CSFR-driven maturational programming is not achieved when less than three quarters of the available G-CSFR dimers are capable of providing this signal. [38][39][40] In addition, yet unknown signaling functions of the novel tyrosine motif in the carboxyterminus of the class IV isoform may also contribute an antimaturational signal by either the homodimer or heterodimer. Studies are ongoing which examine the signaling events initiated by this tyrosine motif and the relative stability of the class I and class IV G-CSFR proteins.…”

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

“…Up to 30% of patients with severe congenital neutropenia (SCN) carry nonsense truncation mutations predicted to lead to the loss of the carboxyterminal-negative regulatory domain potentially leading to enhanced CSF3-induced proliferative responses in myeloid progenitors [24,25]. Such mutations are now known to be acquired somatic mutations and occur in conjunction with inherited mutations in SCN (such as ELANE), are associated with, but not necessary for, the <10% immature granulocytes and <2% myeloblasts without dysgranulopoiesis 1 3 10 9 /L absolute monocyte count or <10% monocytes 3.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…[4][5][6][7][8][9] Furthermore overexpression of vascular endothelial growth factor receptor (VEGF-R) and NRAS mutations have been observed in AML, which could also result in initiation of these pathways. 10,11 Upregulation of the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/ mTOR pathways and phosphorylation of the downstream target Bad are observed frequently in AML patient specimens and associated with a poorer prognosis than patients lacking these changes.…”