Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Li, Zhaoyang; Younger, Kenisha; Gartenhaus, Ronald B.; Joseph, Ann Mary; Hu, Fang; Baer, Maria R.; Brown, Patrick; Dávila, Eduardo

doi:10.1172/jci75821

Cited by 63 publications

(67 citation statements)

References 64 publications

(86 reference statements)

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“…The identification of humans with mutations affecting other components of the TIR pathway should clarify the relative contributions of each human IRAK protein to host defense. These findings are important, given current efforts to develop inhibitors of IRAK-1 and IRAK-4 for the treatment of various human diseases (108,109).…”

Section: Discussionmentioning

confidence: 94%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4-or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM 2 CSK 4 , LTA, FSL-1), TLR1/2 (PAM 3 CSK 4 ), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.IRAK-1 | IRAK-4 | Toll-like receptor | interleukin-1 receptor | primary immunodeficiency

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Section: Discussionmentioning

confidence: 94%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The higher expression of IL-1 pathway components in MLL-translocated ALL leukemia patient cells, and the increased Irak1 and Irak4 expression in mouse models, correlate with the low abundance of wild-type MLL protein in MLL leukemia cells (Figure 1A–B and S1C). The IRAK1/4 inhibitor has recently been shown to sensitize a subset of MDS and T-ALL cells that exhibit high expression of IRAK1 to BCL2 inhibitor treatment, although IRAK1/4 inhibitor alone does not substantially impair these cells (Li et al, 2015; Rhyasen et al, 2013). Here, we found profound effects of IRAK inhibition alone for MLL leukemia both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Liang

Volk

Haug

et al. 2017

Cell

116

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SUMMARY Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation and down-regulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the Super Elongation Complex. Pharmacologically inhibiting this pathway substantially delays progression and improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and therefore relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.

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“…C57BL/6 mice, B6.Ly5.1, B6.129P2(C)-Ccr7tm1Rfor/J (CCR7-deficient), and NSG mice were from Jackson Laboratories (Bar Harbor, ME) 1. B6.CARMA1-deficient mice were gift from Dr. Marisa Alegre (University of Chicago).…”

Section: Methodsmentioning

confidence: 99%

CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

et al. 2016

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Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Cited by 63 publications

References 64 publications

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

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