The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

Mishra, Bibhu Prasad; Yang, Weiwei; Zaffuto, Kristin M.; Artinger, Erika L.; Li, Bin E.; Cheng, Chao; Org, Tõnis; Mikkola, Hanna; Djabali, Malek; Ernst, Patricia

doi:10.1016/j.exphem.2014.07.061

Cited by 25 publications

(32 citation statements)

References 31 publications

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“…D Graphic representation of the direct correlation existing between the percentage of blast cells and the percentage of Che-1 expressing cells, evaluated by FACS analysis. E Distribution of Che-1 expression (arbitrary units, AU) in the total number of HBMs (15), BCP-ALL BMs (80), BCP-ALL/REMISSION (28), and RELAPSE (14). ***P ≤ 0.001 by Mann-Whitney U-test.…”

Section: Resultsmentioning

confidence: 99%

“…abrogation in both NALM-6 and LAL-B #2 cell lines (Figs 6E and F, and EV4G). Among the most downregulated genes in both Che-1and c-Myc-silenced cellular contexts, there was MLL1 (myeloid/ lymphoid or mixed-lineage leukemia-1), which plays an essential role in regulating gene expression during both normal and adult hematopoiesis, and ANP32B (acidic nuclear phosphoprotein 32 family member B), implicated in a number of cellular processes including proliferation and differentiation [28,29]. Consistent with the above results, NALM-6 cells with reduced c-Myc expression exhibited low mRNA levels of MLL1 and ANP32B genes, whereas Che-1 ectopic expression was able to counteract the effect of c-Myc depletion (Fig 6G).…”

Section: Che-1 Is a C-myc Target Genementioning

confidence: 99%

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Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Folgiero

Socolovschi²,

Pallocca³

et al. 2018

EMBO Reports

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Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.

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Section: Resultsmentioning

confidence: 99%

Section: Che-1 Is a C-myc Target Genementioning

confidence: 99%

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Folgiero

Socolovschi²,

Pallocca³

et al. 2018

EMBO Reports

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“…Loss of normal catalytic activity by the fusion protein necessitates the maintenance of a single wild‐type allele of MLL1 for leukemogenesis . However, this effect is not dependent solely on the histone methyltransferase (HMT) activity of MLL1, as MLL1 fusion proteins also require wild‐type MLL1 prebinding to the HoxA9 locus for stable association . Taken together, this suggests that wild‐type MLL1 activity is required for the full transformative capacity of MLL fusion proteins and that targeting the catalytic activity of MLL1 may be an attractive mechanism for cancer chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting human SET1/MLL family of proteins

et al. 2017

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The SET1 family of proteins, and in particular MLL1, are essential regulators of transcription and key mediators of normal development and disease. Here, we summarize the detailed characterization of the methyltransferase activity of SET1 complexes and the role of the key subunits, WDR5, RbBP5, ASH2L, and DPY30. We present new data on full kinetic characterization of human MLL1, MLL3, SET1A, and SET1B trimeric, tetrameric, and pentameric complexes to elaborate on substrate specificities and compare our findings with what has been reported before. We also review exciting recent work identifying potent inhibitors of oncogenic MLL1 function through disruption of protein–protein interactions within the MLL1 complex.

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“…Another histone methyltransferase that is involved in haematopoiesis is MLL, a member of the thritorax complex that catalyses the methylation of lysine 4 at histone 3 (H3K4) . Embryonic deletion of MLL results in reduced numbers of foetal HSCs . The long‐term quiescent pool of HSCs is reduced, and their ability to restore a functional hematopoietic system when transplanted into lethally irradiated mice is significantly impaired.…”

Section: Epigenetics Of Adult Stem Cells and Adult Progenitorsmentioning

confidence: 99%

“…Interestingly, deletion of MLL in adult hematopoietic cells does not affect HSC numbers, but these MLL‐deficient HSCs remain incapable of regenerating blood cells in irradiated recipients . Intriguingly, this phenotype is not dependent on the ability of MLL to methylate histone H3 on MLL target genes but rather on its interaction with the histone H4K16 methyltransferase MOF, suggesting that the cooperation of two chromatin remodelling factors is essential for HSC activity .…”

Section: Epigenetics Of Adult Stem Cells and Adult Progenitorsmentioning

confidence: 99%

Epigenetic regulation of adult stem cell function

Rinaldi

Benitah

2014

The FEBS Journal

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Understanding the cellular and molecular mechanisms that specify cell lineages throughout development, and that maintain tissue homeostasis during adulthood, is paramount towards our understanding of why we age or develop pathologies such as cancer. Epigenetic mechanisms ensure that genetically identical cells acquire different fates during embryonic development and are therefore essential for the proper progression of development. How they do so is still a matter of intense investigation, but there is sufficient evidence indicating that they act in a concerted manner with inductive signals and tissue‐specific transcription factors to promote and stabilize fate changes along the three germ layers during development. In consequence, it is generally hypothesized that epigenetic mechanisms are also required for the continuous maintenance of cell fate during adulthood. However, in vivo models in which different epigenetic factors have been depleted in different tissues do not show overt changes in cell lineage, thus not strongly supporting this view. Instead, the function of some of these factors appears to be primarily associated with tissue functionality, and a strong causal relationship has been established between their misregulation and a diseased state. In this review, we summarize our current knowledge of the role of epigenetic factors in adult stem cell function and tissue homeostasis.

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The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

Cited by 25 publications

References 31 publications

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

Targeting human SET1/MLL family of proteins

Epigenetic regulation of adult stem cell function

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