The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

11q23 rearrangements in de novo childhood acute myeloid leukemia

Review on 11q23 rearrangements in de novo childhood acute myeloid leukemia, with data on clinics, and the genes involved

Targeted treatment options for paediatric B-cell precursor acute lymphoblastic leukaemia patients with constitutional or somatic chromosome 21 alterations

\ua9 2024 The AuthorsBackground: Chromosome 21 is affected in ∼60% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients and includes somatic and constitutional gains, intrachromosomal amplification of chromosome 21 (iAMP21), and the translocation t(12;21) resulting in the ETV6::RUNX1 gene fusion. Methods: Since these numeric and structural chromosome 21 alterations are not targetable, we studied the type and frequency of yet-proven targetable events co-occurring with chromosome 21 alterations. Results: Among 307 primary paediatric BCP-ALL cases, JAK/STAT pathway lesions were most frequent in patients with constitutional gain of chromosome 21 (Down syndrome ALL; 35/71, 49%) and iAMP21 (9/22, 41%). RAS pathway lesions were most frequent in high hyperdiploidy (62/108, 57%) and FLT3 lesions were most frequent in iAMP21 (7/22, 32%). Virtually all cases expressed CD19 and CD22 at the cell surface. Positivity for CD20 surface expression ranged from 67% in iAMP21 (8/12) to 20% in ETV6::RUNX1 (26/129). Conclusion: Activated JAK/STAT, RAS or FLT3 signalling, and CD marker surface expression may provide targetable treatment options for the majority of chromosome 21-altered BCP-ALL cases

On the kinematics of the Local cosmic void

We collected the existing data on the distances and radial velocities of galaxies around the Local Void in the Aquila/Hercules to examine the peculiar velocity field induced by its underdensity. A sample of 1056 galaxies with distances measured from the Tip of the Red Giant Branch, the Cepheid luminosity, the SNIa luminosity, the surface brightness fluctuation method, and the Tully-Fisher relation has been used for this purpose. The amplitude of outflow is found to be ~300 km/s. The galaxies located within the void produce the mean intra-void number density about 1/5 of the mean external number density of galaxies. The void's population has a lower luminosity and a later morphological type with the medians: M_B = -15.7^m and T = 8 (Sdm), respectively.Comment: Version 1. 14 pages, 8 figures, 2 tables. Accepted to Astrophysics, Volume 54, Issue

Stellar feedback in a clumpy galaxy at z ∼ 3.4

Giant star-forming regions (clumps) are widespread features of galaxies at z ≈ 1−4. Theory predicts that they can play a crucial role in galaxy evolution, if they survive to stellar feedback for >50 Myr. Numerical simulations show that clumps’ survival depends on the stellar feedback recipes that are adopted. Up to date, observational constraints on both clumps’ outflows strength and gas removal time-scale are still uncertain. In this context, we study a line-emitting galaxy at redshift z ≃ 3.4 lensed by the foreground galaxy cluster Abell 2895. Four compact clumps with sizes ≲280 pc and representative of the low-mass end of clumps’ mass distribution (stellar masses ≲2 × 108 M⊙) dominate the galaxy morphology. The clumps are likely forming stars in a starbursting mode and have a young stellar population (∼10 Myr). The properties of the Lyman-α (Lyα) emission and nebular far-ultraviolet absorption lines indicate the presence of ejected material with global outflowing velocities of ∼200–300 km s−1. Assuming that the detected outflows are the consequence of star formation feedback, we infer an average mass loading factor (η) for the clumps of ∼1.8–2.4 consistent with results obtained from hydrodynamical simulations of clumpy galaxies that assume relatively strong stellar feedback. Assuming no gas inflows (semiclosed box model), the estimates of η suggest that the time-scale over which the outflows expel the molecular gas reservoir (≃7 × 108 M⊙) of the four detected low-mass clumps is ≲50 Myr

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

\ua9 The Author(s) 2024.Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease

Group membership and racial bias modulate the temporal estimation of in-group/out-group body movements

Social group categorization has been mainly studied in relation to ownership manipulations involving highly-salient multisensory cues. Here, we propose a novel paradigm that can implicitly activate the embodiment process in the presence of group affiliation information, whilst participants complete a task irrelevant to social categorization. Ethnically White participants watched videos of White- and Black-skinned models writing a proverb. The writing was interrupted 7, 4 or 1 s before completion. Participants were tasked with estimating the residual duration following interruption. A video showing only hand kinematic traces acted as a control condition. Residual duration estimates for out-group and control videos were significantly lower than those for in-group videos only for the longest duration. Moreover, stronger implicit racial bias was negatively correlated to estimates of residual duration for out-group videos. The underestimation bias for the out-group condition might be mediated by implicit embodiment, affective and attentional processes, and finalized to a rapid out-group categorization

Galaxies appear simpler than expected

Galaxies are complex systems the evolution of which apparently results from the interplay of dynamics, star formation, chemical enrichment, and feedback from supernova explosions and supermassive black holes. The hierarchical theory of galaxy formation holds that galaxies are assembled from smaller pieces, through numerous mergers of cold dark matter. The properties of an individual galaxy should be controlled by six independent parameters including mass, angular-momentum, baryon-fraction, age and size, as well as by the accidents of its recent haphazard merger history. Here we report that a sample of galaxies that were first detected through their neutral hydrogen radio-frequency emission, and are thus free of optical selection effects, shows five independent correlations among six independent observables, despite having a wide range of properties. This implies that the structure of these galaxies must be controlled by a single parameter, although we cannot identify this parameter from our dataset. Such a degree of organisation appears to be at odds with hierarchical galaxy formation, a central tenet of the cold dark matter paradigm in cosmology.Comment: 26 pages, 14 figure