Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

Abstract

Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways. The role of genomic instability in the pathogenesis of FLT3 ITD AML warrants further examination as it offers potential therapeutic targets.

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents

“…Several studies have recently demonstrated a pervasive dysregulation of genomic stability in several cancers, including AML. 8 , 38 To explore whether observed high SIRT6 expression was related to the constitutive DNA damage and intense replicative stress observed in AML cells, we used a chromosomal instability signature (CIN)16 to categorize AML cell lines included in a published dataset (GSE59808). A subset of approximately 40% AML cell lines demonstrated overexpression of probe sets belonging to CIN-signature ( Figure 5A ).…”

Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR–CCNB3 gene fusion

“…ITDs constitute a rare category of gene mutations in which a segment of a coding region of a gene is duplicated in an end‐to‐end manner. Although the exact mechanism remains unclear, several studies have suggested genomic instability accompanied by erroneous DNA repair mechanisms to be key elements contributing to this phenomenon . Very recently, an epidermal growth factor receptor ( EGFR ) ITD was reported in a DN CCSK originating from a horseshoe kidney.…”

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

“…These effectors interact with the PI3K/Akt/mTOR pathway, elucidation of which may reveal possible mechanisms of resistance to PI3K-directed therapies. Recent studies have stressed that FLT3-ITD induces genomic instability through ROS production, which potentially contributes to chemoresistance leading to disease relapse [132,133]. The PI3K/Akt/mTOR signaling pathway is linked to both ROS production and the DNA damage response (DDR) pathway, strengthening the premise of further exploiting this pathway as a potential therapeutic target [46,134,135].…”

“…In a previous section, we briefly highlighted the importance of increased ROS in AML, which can promote genomic instability and contributes to chemotherapy resistance. In particular, there is increasing evidence associating FLT3 mutations with DNA damage, specifically through increased ROS, resulting in double strand breaks (DSBs) and impaired DNA repair [132,306]. Targeting DNA damage repair mechanisms may provide a novel therapeutic opportunity in AML that may reduce repair errors and genomic instability [307].…”