Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice

Abstract

Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis.

TAK1 control of cell death

“…For example, Tak1-deficient neutrophils hyperproliferate rather than dying spontaneously, leading to splenomegaly and myelomonocytic leukemia. 87,89 Although TAK1 is known as an activator of NF-kB and p38 MAPK, Tak1 deletion in neutrophils increases activity of these downstream factors, which warrants further mechanistic analysis. Finally, we recently show that Tab2 deletion exaggerates wound-induced cell death and delays wound healing in vivo.…”

“…Lethal E10-11 8,25,119 (Epidermis) Increased cell death-4Lethal P5-7 82 (Intestinal epithelium) Increased cell death-4Lethal P0 55 (Inducible intestinal epithelium) Ileitis and loss of paneth cells 55,65 (Endothelium/blood vessel) Increased cell death, defective vascularization-4Lethal E10-11 37 (Liver) Increased cell death-4Hepatocellular carcinoma within 6 weeks of age 57,83 (Hematopoietic system) Increased cell death-4Depletion of stem cells [84][85][86] (Myeloid) Macrophage death, splenomegaly and hyperproliferation of neutrophils 87,89 Tab1 Lethal E15-16 120 There is a well-studied inhibitory regulation from apoptosis to necroptosis (Figure 4, blue inhibition arrow). Thus, inhibition of caspase-8 activates necroptosis.…”

Chronic myelomonocytic leukemia: Forefront of the field in 2015

“…Another model where mice developed CMML-like features was created with conditionally deleted TGF-β activated kinase 1 (Tak1) in the myeloid compartment [96]. Mice with myeloid-deficient Tak1 developed a myelomonocytic expansion, splenomegaly, and murine AML as they aged [96].…”

“…Mice with myeloid-deficient Tak1 developed a myelomonocytic expansion, splenomegaly, and murine AML as they aged [96]. The deletion appeared to affect cytokine mediated signaling, and was associated with genomic instability [96].…”

“…Mice with myeloid-deficient Tak1 developed a myelomonocytic expansion, splenomegaly, and murine AML as they aged [96]. The deletion appeared to affect cytokine mediated signaling, and was associated with genomic instability [96]. In another recently developed mouse model, deletion of transcription intermediary factor 1γ ( Tif1g ) initiated age-dependent development of myeloproliferation reminiscent of CMML [97].…”