An aberrantly sustained emergency granulopoiesis response accelerates postchemotherapy relapse in MLL1-rearranged acute myeloid leukemia in mice

Abstract

<jats:p>Acute myeloid leukemia (AML) with mixed lineage leukemia 1 (<jats:italic>MLL1</jats:italic>) gene rearrangement is characterized by increased expression of a set of homeodomain transcription factors, including homeobox A9 (HOXA9) and HOXA10. The target genes for these regulators include fibroblast growth factor 2 (<jats:italic>FGF2</jats:italic>) and Ariadne RBR E3 ubiquitin ligase 2 (<jats:italic>ARIH2</jats:italic>). FGF2 induces leukemia stem cell expansion in MLL1-rearranged AML. ARIH2 encodes TRIAD1, an E3 ubiquitin ligase required for termination of emergency granulopoiesis and leukemia suppressor function in <jats:italic>MLL1</jats:italic>-rearranged AML. Receptor tyrosine kinases (RTKs), including the FGF receptor, are TRIAD1 substrates that are possibly relevant to these activities. Using transcriptome analysis, we found increased activity of innate immune response pathways and RTK signaling in bone marrow progenitors from mice with <jats:italic>MLL1</jats:italic>-rearranged AML. We hypothesized that sustained RTK signaling, because of decreased TRIAD1 activity, impairs termination of emergency granulopoiesis during the innate immune response and contributes to leukemogenesis in this AML subtype. Consistent with this, we found aberrantly sustained emergency granulopoiesis in a murine model of <jats:italic>MLL1</jats:italic>-rearranged AML, associated with accelerated leukemogenesis. Treating these mice with an inhibitor of TRIAD1-substrate RTKs terminated emergency granulopoiesis, delayed leukemogenesis during emergency granulopoiesis, and normalized innate immune responses when combined with chemotherapy. Emergency granulopoiesis also hastened postchemotherapy relapse in mice with <jats:italic>MLL1</jats:italic>-rearranged AML, but remission was sustained by ongoing RTK inhibition. Our findings suggest that the physiological stress of infectious challenges may drive AML progression in molecularly defined subsets and identify RTK inhibition as a potential therapeutic approach to counteract this process.</jats:p>

Prolonged generation of multi-lineage blood cells in wild-type animals from pluripotent stem cells

“…Point mutations, amplifications, and translocations of Runx1 are often associated with leukemia ( De Braekeleer et al., 2009 ; Niini et al., 2000 ; Osato, 2004 ; Otalora-Otalora et al., 2019 ). Hoxa9 and Hoxa10 are highly expressed in acute myeloid leukemias ( Collins and Hess, 2016 ; Lambert et al., 2019 ; Shah et al., 2016 ; Wang et al., 2020 ). Interestingly, the iR1A9A10-ESC-derived iHPC recipients showed no leukemogenesis and tumors over time.…”

E3 ubiquitin ligases in the acute leukemic signaling pathways

“…The genetic characteristic of MLL is the chromosome 11q23 abnormality, Frontiers in Physiology frontiersin.org and this type of leukemia is associated with adverse prognosis. Emergency granulopoiesis is known to accelerate leukemogenesis in MLL1-rearranged AML and this occurs in an RTK-dependent manner (Wang et al, 2020). Moreover, it has been reported that in MLL1-ELL AML mice, TRIAD1 expression is decreased, contributing to sustained RTK signaling and failing to terminate emergency granulopoiesis (Figure 4) (Wang et al, 2018;Wang et al, 2020).…”

“…Emergency granulopoiesis is known to accelerate leukemogenesis in MLL1-rearranged AML and this occurs in an RTK-dependent manner (Wang et al, 2020). Moreover, it has been reported that in MLL1-ELL AML mice, TRIAD1 expression is decreased, contributing to sustained RTK signaling and failing to terminate emergency granulopoiesis (Figure 4) (Wang et al, 2018;Wang et al, 2020). Using TRIAD1-substrate RTKs inhibitors can terminate emergency granulopoiesis, delay leukemogenesis during emergency granulopoiesis, and normalize innate immune responses when combined with chemotherapy (Table 2) (Wang et al, 2020).…”

“…Moreover, it has been reported that in MLL1-ELL AML mice, TRIAD1 expression is decreased, contributing to sustained RTK signaling and failing to terminate emergency granulopoiesis (Figure 4) (Wang et al, 2018;Wang et al, 2020). Using TRIAD1-substrate RTKs inhibitors can terminate emergency granulopoiesis, delay leukemogenesis during emergency granulopoiesis, and normalize innate immune responses when combined with chemotherapy (Table 2) (Wang et al, 2020). In addition, as a RTK inhibitor, nintedanib can reverse activation (phosphorylation) of AKT in MLL1-ELL + LIN − cells that are associated with inhibited GSK3β phosphorylation and β-catenin destabilization (Wang et al, 2020).…”

“…Using TRIAD1-substrate RTKs inhibitors can terminate emergency granulopoiesis, delay leukemogenesis during emergency granulopoiesis, and normalize innate immune responses when combined with chemotherapy (Table 2) (Wang et al, 2020). In addition, as a RTK inhibitor, nintedanib can reverse activation (phosphorylation) of AKT in MLL1-ELL + LIN − cells that are associated with inhibited GSK3β phosphorylation and β-catenin destabilization (Wang et al, 2020).…”