The Leukemia-associated Mll-Ell Oncoprotein Induces Fibroblast Growth Factor 2 (Fgf2)-dependent Cytokine Hypersensitivity in Myeloid Progenitor Cells

Shah, Chirag; Bei, Ling; Wang, Hao; Platanias, Leonidas C.; Eklund, Elizabeth A.

doi:10.1074/jbc.m113.496109

Cited by 17 publications

(33 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytokine-induced phosphorylation of conserved, homeodomain tyrosine residues in HoxA9 and HoxA10 mediates these differentiation-specific effects (34-37). In contrast, we found cooperative, phosphorylation-independent activation of FGF2 transcription by HoxA9 and HoxA10 (27,38). Fgf2 (fibroblast growth factor 2) is involved in expansion of bone marrow progenitor cells, but also primes granulocytes for NADPH-oxidase activity (27,38-40).…”

Section: Introductioncontrasting

confidence: 64%

“…In contrast, we found cooperative, phosphorylation-independent activation of FGF2 transcription by HoxA9 and HoxA10 (27,38). Fgf2 (fibroblast growth factor 2) is involved in expansion of bone marrow progenitor cells, but also primes granulocytes for NADPH-oxidase activity (27,38-40). E selectin is another a phagocyte effector and common HoxA9/HoxA10-target gene (41).…”

Section: Introductioncontrasting

confidence: 64%

“…Fgf-R1 was of interest for several reasons. First, Fgf2-binding to Fgf-R1 enhances proliferation of progenitor cells, but also primes mature granulocytes for activation (27,38-40). Second, HoxA10 activates FGF2 transcription, but does not influence Fgf-R1 mRNA (27).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to these genes, HoxA9 and HoxA10 cooperate to activate the FGF2 gene in a manner that is not influenced by tyrosine phosphorylation ( 27,38 ). Instead, our current studies suggest that HoxA10 regulates the effects of Fgf2 via Triad1-induced ubiquitination and degradation of Fgf-R1.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1

Wang

Bei

Shah

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Expression of the E3 ubiquitin ligase Triad1 is greater in mature granulocytes than in myeloid progenitor cells. HoxA10 actives transcription of the gene encoding Triad1 (ARIH2) during myeloid differentiation, but the contribution of increased Triad1 expression to granulocyte production or function is unknown. Mice with bone marrow-specific disruption of the ARIH2 gene exhibit constitutive inflammation with tissue infiltration by granulocytes and B-cells. In contrast, disruption of the HOXA10 gene in mice neither constitutively activates the innate immune response nor significantly alters steady state granulopoiesis. Our current study explores the impact of HoxA10-induced Triad1 expression on emergency (stress) granulopoiesis. We found that mice with HOXA10 gene disruption exhibited an overwhelming and fatal emergency granulopoiesis response that was characterized by tissue infiltration with granulocytes, but reversed by re-expression of Triad1 in the bone marrow. We determined that HoxA9 repressed ARIH2 transcription in myeloid progenitor cells; antagonizing the effect of HoxA10 on Triad1 expression. And, we found that differentiation-stage-specific ARIH2 transcription was regulated by the tyrosine phosphorylation states of HoxA9 and HoxA10. Our studies demonstrate a previously undescribed role for HoxA10 in terminating emergency granulopoiesis; suggesting an important contribution by Hox proteins to the innate immune response.

show abstract

Section: Introductioncontrasting

confidence: 64%

Section: Introductioncontrasting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1

Wang

Bei

Shah

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…12,13 In addition, the anti-apoptotic protein BCL2 (B-cell lymphoma) and the growth factor FGF2 (fibroblast growth factor) are regulated by HOX proteins. 14,15 Apart from these examples and despite the discovery of numerous HOXA9-binding sites across the genome by chromatin immunoprecipitation-sequencing ChIP-Seq, 16 functionally characterized HOX targets are scarce.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor 1 is a direct HOXA9 target important for hematopoietic transformation

Steger

et al. 2014

Leukemia

View full text Add to dashboard Cite

HOX homeobox proteins are key oncogenic drivers in hematopoietic malignancies. Here we demonstrate that HOXA1, HOXA6 and predominantly HOXA9 are able to induce the production of insulin-like growth factor 1 (Igf1). In chromatin immunoprecipitations, HOXA9 bound directly to the putative promoter and a DNase-hypersensitive region in the first intron of the Igf1 gene. Transcription rates of the Igf1 gene paralleled HOXA9 activity. Primary cells transformed by HOXA9 expressed functional Igf1 receptors and activated the protein kinase Akt in response to Igf1 stimulation, suggesting the existence of an autocrine signaling loop. Genomic deletion of the Igf1 gene by Cre-mediated recombination increased sensitivity toward apoptosis after serum starvation. In addition, the leukemogenic potential of Igf1-negative, HOXA9-transformed cells was impaired, leading to a significant delay in disease development on transplantation into recipient animals.

show abstract

A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy

et al. 2022

View full text Add to dashboard Cite

We investigated the safety and efficacy of nintedanib added to low-dose cytarabine (LDAC) in a phase 1/2 study in patients 60 years or older with newly diagnosed or relapsed/refractory (r/r) AML ineligible for intensive chemotherapy. The results of the dose-finding phase 1 part have been previously published. Patients were randomized 1:1 to LDAC plus nintedanib or LDAC plus placebo stratified by AML status (newly diagnosed vs r/r). LDAC was applied subcutaneously at 20 mg twice daily on days 1 to 10. Nintedanib/placebo was orally administered twice daily on days 1 to 28 in 28-day cycles. The primary endpoint was overall survival (OS). Between 05/2017 and 09/2019, 31 patients were randomized and 30 were treated, before the study was terminated prematurely due to slow recruitment. Median (range) age of patients was 76 (60–84) years. Twenty-two patients (73%) had r/r AML. Median OS in patients treated with LDAC and nintedanib was 3.4 months, compared with 3.6 months in those treated in the placebo arm, with a HR adjusted for AML status of 1.19 (corresponding confirmatory adjusted 95% CI, 0.55–2.56; univariate log-rank P = 0.96). In the 22 patients with r/r AML, median OS was 3.0 months in the nintedanib and 3.6 months in the placebo arm (P = 0.36). One patient in the nintedanib and two patients in the placebo arm achieved a CR and entered maintenance treatment. Nintedanib showed no superior therapeutic activity over placebo when added to LDAC in elderly AML patients considered unfit for intensive chemotherapy. The trial was registered at clinicaltrials.gov NCT01488344.

show abstract

The Leukemia-associated Mll-Ell Oncoprotein Induces Fibroblast Growth Factor 2 (Fgf2)-dependent Cytokine Hypersensitivity in Myeloid Progenitor Cells

Cited by 17 publications

References 48 publications

HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1

HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1

Insulin-like growth factor 1 is a direct HOXA9 target important for hematopoietic transformation

A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy

Contact Info

Product

Resources

About