RUNX1 regulates corepressor interactions of PU.1

Hu, Zhenbo; Gu, Xiaorong; Baraoidan, Kristine; Ibanez, Vinzon; Sharma, Arun K.; Kadkol, Shrihari S.; Munker, Reinhold; Ackerman, Steven J.; Nucifora, Giuseppina; Saunthararajah, Yogen

doi:10.1182/blood-2010-10-312512

Cited by 51 publications

(62 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, PU.1 also blocks expression of genes associated with other variant cell fates, such as Gata2, Zbtb16, Prf1, and probably Il2rb, which could promote mast cell, innate lymphocyte, or NK cell pathways that are much less Notch-dependent. PU.1 is capable of acting as a direct repressor (Rekhtman et al 2003;Stopka et al 2005;Hu et al 2011;Wontakal et al 2012;de la Rica et al 2013), and our results suggest that it down-regulates Sox13 and Il7r directly. However, its repressive effects on most T-cell genes work through an indirect mechanism.…”

Section: Discussionsupporting

confidence: 62%

Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1

et al. 2015

View full text Add to dashboard Cite

The ETS family transcription factor PU.1 is essential for the development of several blood lineages, including T cells, but its function in intrathymic T-cell precursors has been poorly defined. In the thymus, high PU.1 expression persists through multiple cell divisions in early stages but then falls sharply during T-cell lineage commitment. PU.1 silencing is critical for T-cell commitment, but it has remained unknown how PU.1 activities could contribute positively to T-cell development. Here we employed conditional knockout and modified antagonist PU.1 constructs to perturb PU.1 function stage-specifically in early T cells. We show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression such that removal or antagonism of endogenous PU.1 allows precocious access to T-cell differentiation. Dominant-negative effects reveal that this repression by PU.1 is mediated indirectly. Genome-wide transcriptome analysis identifies novel targets of PU.1 positive and negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. Thus, in addition to supporting early T-cell proliferation, PU.1 regulates the timing of activation of the core T-lineage developmental program.

show abstract

Section: Discussionsupporting

confidence: 62%

Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m stem cell transcription factors (e.g., HLF and HOXB4) and activate stem cell genes and stem cell fate in response to the same treatments (good therapeutic index) (10,14,17,(20)(21)(22)(23).…”

Section: Methodsmentioning

confidence: 99%

“…These differentiation-mediated cell-cycle exits, like those that occur during normal tissue differentiation, do not require p53 and are readily induced in p53/p16-null cancer cells (10,(14)(15)(16). The same chromatin-relaxing conditions increase the differentiation of normal progenitors as well (17,18) but, in contrast, increase self-renewal of NHSCs (10,14,17,(19)(20)(21)(22)(23)(24). The reasons for this cell context-dependent response have been evaluated: differentiation is driven by relatively few master transcription factors (25).…”

Section: Methodsmentioning

confidence: 99%

“…The reasons for this cell context-dependent response have been evaluated: differentiation is driven by relatively few master transcription factors (25). Myeloid cancer cells express master myeloid differentiation-driven transcription factors (e.g., CEBPA and PU.1) at high levels, yet the target genes of these transcription factors are epigenetically silenced (10,13,14,20,(26)(27)(28)(29) because of aberrant recruitment of silencing -instead of activating -chromatin-modifying enzymes to the transcription factors (20,27,30). Inhibition of silencing enzymes with drugs such as decitabine restores expression of numerous target genes of the transcription factors, including MYC antagonists (e.g., CEBPE and p27/ CDKN1B), that terminate proliferation (10, 14, 17, 20-22, 27, 30-32).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Saunthararajah¹,

Sekeres²,

Advani³

et al. 2015

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

IntroductionAlthough conventional cytotoxic treatments for myeloid cancers can have differing proximal actions, e.g., topoisomerase inhibition (daunorubicin) or termination of DNA chain synthesis (cytarabine), a final common pathway converges onto p53 (TP53), a master regulator of apoptosis (cytotoxicity) (reviewed in ref. 1). As such, TP53 mutation or deletion is associated with resistance to cytotoxic treatments in vitro (2, 3) and in vivo: TP53-mutated acute myeloid leukemia (AML) treated with daunorubicin and/ or cytarabine had a response rate of 33% compared with 81% for TP53 WT AML, while TP53-mutated myelodysplastic syndromes (MDS) had a response rate of 8% versus 60% for MDS with WT TP53 (4). The poorest-risk MDS and AML subtypes, e.g., MDS and AML with complex cytogenetic abnormalities, have the highest rate of TP53 mutations, exceeding 70% in some series (5). Even if TP53 itself is not mutated, alterations in other key p53-system BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cellcycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS.In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m 2 /day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4-to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS.The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed b...

show abstract

“…Besides being part of such a feed-forward loop driving differentiation, high PU.1 levels and thus commitment towards the myeloid lineages are achieved via lengthening of the cell cycle and ensuing protein accumulation [54]. As the end-product of these developmentally controlled activities, PU.1 and RUNX1 function synergistically by forming a complex that excludes co-repressors [55] in myeloid cells, ultimately resulting in the regulation of lineage-specific genes such as the CSF-1 receptor gene (Csf1r) [56] and Ig-like transcripts [57]. Finally, RUNX1 is also capable of recruiting Polycomb repressive complex 1 (PRC1) to regulatory elements of myeloid genes [58].…”

Section: Developmental-stage-specific Runx1 and Pu1 Functionmentioning

confidence: 99%