Table 3. Experimental evidence for IRAK1 involvement in hematologic malignancies.
| Tumor Type | Experimental System | Effector(s) | Effects |
|---|---|---|---|
| AML [36] | Primary AML cells | Pacritinib | Antiproliferative, cytotoxic effects in patient AML cells via IRAK1, not JAK2 or FLT3; IRAK1 kinase domain mutations conferred pacritinib resistance. |
| AML [161] | Patients with AML | Pacritinib | Clinical benefit (stable disease or better) in 3/7 (43%) patients with AML. |
| T-ALL [44] | Primary T-ALL cells; NSG T-ALL mouse model | IRAK1/4 inhibitor I; IRAK1 shRNA, IRAK4 shRNA | Primary AML cells have high IRAK1 mRNA levels; IRAK 1 and/or 4 inhibition is antiproliferative; IRAK1/4 inhibitor reduces tumor burden and prolongs survival when combined with Bcl-2 inhibitor or vinblastine. |
| MLL [163] | SEM(MLL-AFF1) cell line; MLL-AF9 leukemia mice | IRAK1/4 inhibitor I; “Compound 26” [165] | Both IRAK inhibitors impede proliferation of MLL leukemia cells; both delayed disease progression, improved survival in MLL mouse model. |
| ABC-DLBCL [167] | ABC- and GCB-DLBCL cell lines | IRAK1/4 inhibitor I; IRAK1 shRNA, IRAK4 shRNA | IRAK1/4 inhibitor I, IRAK1 shRNA, cytotoxic to ABC-DLBCL but not GCB-DLBCL cell lines; IRAK1 kinase activity not required for cytotoxicity. |
| ABC-DLBCL [28] | MyD88 L265P ABC-DLBCL cell lines | Jh-X-119-01 | Selective IRAK1 inhibition suppressed NF-κB activation, showed synergy with ibrutinib in killing MyD88 mutated ABC-DLBCL cells. |
| CLL [169] | Patient PBMCs | Pacritinib | Pacritinib significantly impaired monocyte and monocyte-derived macrophage viability, increased apoptosis, and significantly inhibited CLL cell viability, but contribution of IRAK1 inhibition unknown. |
| WM [124] | MyD88 L265P cell lines | IRAK1/4 inhibitor I | IRAK1/4 inhibitor I decreased nuclear NF-κB staining, phosphorylation of NF-κB and IκBα in mutated but not wild-type Myd88 cells. |
| WM [173] | MyD88 L265P cell lines | IRAK1/4 inhibitor I | IRAK1/4 inhibitor I was synergistic with ibrutinib in MyD88 L265P cells and enhanced cell killing relative to either single agent. |
| WM [28] | MyD88 L265P WM cell lines | Jh-X-119-01 | Selective IRAK1 inhibition suppressed NF-κB activation, and showed synergy with ibrutinib in killing MyD88 mutated WM cells. |
| FL [174] | Patient biopsy tissue | N/A | IRAK1 is 1 of the 2 most significant predictors of FL transformation to more aggressive disease. |
| MDS [176] | MiR-146a -/- mice | MiR-146a | MiR-146 knockout mice display an MDS-like phenotype. |
| MDS [177] | MiR-146a -/- mice | MiR-146a | MiR-146a regulates HSC homeostasis independently of Traf6 expression; Irak1 is a candidate. |
| MDS [178] | Patient tissue samples; MDS cell lines; NSG MDS xenograft mice | NA | IRAK1 overexpressed in 20–30% of patients, hyperactivated in BM samples in the majority of patients; IRAK1 expression correlates with poor survival (P = 0.035); IRAK1/4 inhibitor I is antiproliferative in MDS progenitor cells, ameliorates disease in MDS xenograft mouse model. |
| PEL [186] | KSHV-transfected SLK cells | mIR-K5, mIR-K9 | Both mRNAs downregulate IRAK1 and MyD88, and reduce IL-1α-induced IL-6, IL-8 levels. |
| PEL [187] | PEL cell lines; PEL patient exudates | IRAK1 shRNA | NGS identified common Phe196Ser IRAK1 mutation; IRAK1 shRNA abolished PEL cell growth in culture. |
ABC, activated B-cell like; GCB, germinal center B-cell like; HSC, hematopoietic stem cell; NA, not applicable; NGS, next-generation sequencing.