A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML

Dynamical Decoupling of Nested Bars: Self-Gravitating Gaseous Nuclear Bars

A substantial fraction of barred galaxies host additional nuclear bars which tumble with pattern speeds exceeding those of the large-scale (primary) stellar bars. We have investigated the mechanism of formation and dynamical decoupling in such nested bars which include gaseous (secondary) nuclear bars within the full size galactic disks, hosting a double inner Lindblad resonance. Becoming increasingly massive and self-gravitating, the nuclear bars lose internal (circulation) angular momentum to the primary bars and increase their strength. Developing chaos within these bars triggers a rapid gas collapse -- bar contraction. During this time period, the secondary bar pattern speed Omega_s~a^{-1}, where "a" stands for the bar size. As a result, Omega_s increases dramatically until a new equilibrium is reached (if at all), while the gas specific angular momentum decreases -- demonstrating the dynamical decoupling of nested bars. Viscosity, and therefore the gas presence, appears to be a necessary condition for the prograde decoupling of nested bars. This process maintains an inflow rate of ~1 M_o/yr over ~10^8 yrs across the central 200 pc and has important implications for fueling the nuclear starbursts and AGN.Comment: 7 pages, 4 postscript figures. (The associated MPEG movie can be requested from the authors directly.) Submitted to Astrophysical Journal Letter

Mice Null for Calsequestrin 1 Exhibit Deficits in Functional Performance and Sarcoplasmic Reticulum Calcium Handling

In skeletal muscle, the release of calcium (Ca2+) by ryanodine sensitive sarcoplasmic reticulum (SR) Ca2+ release channels (i.e., ryanodine receptors; RyR1s) is the primary determinant of contractile filament activation. Much attention has been focused on calsequestrin (CASQ1) and its role in SR Ca2+ buffering as well as its potential for modulating RyR1, the L-type Ca2+ channel (dihydropyridine receptor, DHPR) and other sarcolemmal channels through sensing luminal [Ca2+]. The genetic ablation of CASQ1 expression results in significant alterations in SR Ca2+ content and SR Ca2+ release especially during prolonged activation. While these findings predict a significant loss-of-function phenotype in vivo, little information on functional status of CASQ1 null mice is available. We examined fast muscle in vivo and in vitro and identified significant deficits in functional performance that indicate an inability to sustain contractile activation. In single CASQ1 null skeletal myofibers we demonstrate a decrease in voltage dependent RyR Ca2+ release with single action potentials and a collapse of the Ca2+ release with repetitive trains. Under voltage clamp, SR Ca2+ release flux and total SR Ca2+ release are significantly reduced in CASQ1 null myofibers. The decrease in peak Ca2+ release flux appears to be solely due to elimination of the slowly decaying component of SR Ca2+ release, whereas the rapidly decaying component of SR Ca2+ release is not altered in either amplitude or time course in CASQ1 null fibers. Finally, intra-SR [Ca2+] during ligand and voltage activation of RyR1 revealed a significant decrease in the SR[Ca2+]free in intact CASQ1 null fibers and a increase in the release and uptake kinetics consistent with a depletion of intra-SR Ca2+ buffering capacity. Taken together we have revealed that the genetic ablation of CASQ1 expression results in significant functional deficits consistent with a decrease in the slowly decaying component of SR Ca2+ release

Targeting H3K9me3 as Novel Therapeutic Strategy in MLLr‐AML

No abstract available

Targeting H3K9me3 as Novel Therapeutic Strategy in MLLr‐AML

No abstract available

The Histone Demethylase KDM4A Is Required to Sustain H3K9me3/H3K27me3 Epigenetic States and Oncogenesis in MLL-AF9 Acute Myeloid Leukemia

No abstract available

The Histone Demethylase KDM4A Is Required to Sustain H3K9me3/H3K27me3 Epigenetic States and Oncogenesis in MLL-AF9 Acute Myeloid Leukemia

No abstract available