Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34<sup>+</sup>/CD38<sup>−</sup> cells and sensitizes them to antileukemia agents

Ikezoe, Takayuki; Yang, Jing; Nishioka, Chie; Kojima, Shinsuke; Takeuchi, Asako; Koeffler, H. Phillip; Yokoyama, Akihito

doi:10.1002/ijc.25806

Cited by 21 publications

(33 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1E). Further experiments found that the levels of DNMT3A in CD34 + /CD38 − AML cells with an abundant amount of p-STAT5 [6] isolated from patients (n = 8) were 2.8-fold greater than those in their CD34 + /CD38 + counterparts (P = 0.1) (Supplemental Fig. 1).…”

Section: Downregulation Of Stat5a Decreased Levels Of Dnmt3amentioning

confidence: 92%

See 1 more Smart Citation

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

et al. 2015

Self Cite

View full text Add to dashboard Cite

Section: Downregulation Of Stat5a Decreased Levels Of Dnmt3amentioning

confidence: 92%

“…Interestingly, CD34 + /CD38 − cells expressed a greater amount of signal transducer and activator of transcription 5 (STAT5) than their CD34 + /CD38 + counterparts in 10 of 11 cases [6]. STAT5 is involved in various aspects of hematopoiesis, cell proliferation, differentiation, and cell survival [7,8].…”

Section: Introductionmentioning

confidence: 99%

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

et al. 2015

Self Cite

View full text Add to dashboard Cite

“…21 Among the genetic aberrations identified in hematologic malignancies are FLT3, JAK2 and the CDKs. The specific indications that may be suitable for these targets include (a) chronic lymphocytic leukemia, multiple myeloma and mantle cell lymphoma, where CDK inhibitors have shown preliminary clinical efficacy; (b) acute myeloid leukemia, where the FLT3-ITD mutation is present in B30% of the patients 9 and activated JAK2 is an emerging target in both circulating blasts and tumor stem cells; 22,23 and (c) myeloproliferative diseases where JAK2 lesions were identified in 450% of the patients. 24 In this study, we present the preclinical evaluation of a novel chemical entity, TG02, a small molecule that inhibits these oncogenic kinases.…”

Section: Discussionmentioning

confidence: 99%

TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties

et al. 2011

View full text Add to dashboard Cite

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.

show abstract

“…Different JAK2 inhibitors reduce viability of AML cell lines in vitro (59,60). However, clinical studies using the JAK2 inhibitor ruxolitinib resulted in only modest antileukemic efficacy in relapsed/refractory AML patients (26).…”

Section: Discussionmentioning

confidence: 99%

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Murone

Radpour

Attinger

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34þ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34 þ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses.

show abstract

Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34⁺/CD38⁻ cells and sensitizes them to antileukemia agents

Abstract: To verify molecular mechanisms by which leukemia stem cells (LSCs) maintain a dormant state, we explored the activity of the major prosurvival signal pathways in CD34

Cited by 21 publications

References 35 publications

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Contact Info

Product

Resources

About

Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34+/CD38− cells and sensitizes them to antileukemia agents

Abstract: To verify molecular mechanisms by which leukemia stem cells (LSCs) maintain a dormant state, we explored the activity of the major prosurvival signal pathways in CD34

Cited by 21 publications

References 35 publications

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

STAT5A regulates DNMT3A in CD34+/CD38− AML cells

TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Contact Info

Product

Resources

About

Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34⁺/CD38⁻ cells and sensitizes them to antileukemia agents