Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15.

The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.

RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis.

Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor ARID3A by miR-125b is a key event in the pathogenesis of acute megakaryoblastic leukemia (AMKL). AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing the disease. The results of our study showed that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncovered Arid3a as the main miR-125b target behind this synergy. We demonstrated that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFß-induced apoptosis and cell cycle arrest in complex with SMAD2/3. Although Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a blockade of dual megakaryocytic/erythroid differentiation and subsequently of AMKL. Inversely, restoring ARID3A expression relieves the arrest of megakaryocytic differentiation in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of posttranscriptional gene regulation can interact to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.

A study of behaviour profiles among intellectually disabled people in residential care in Hungary.

The authors investigated the behavioural dimensions of 269 intellectually disabled (ID) people in residential care in specialized institutions in Tolna county (South-West Hungary) with the aim of screening the frequency and severity of the relevant behavioural symptoms associated with intellectual disability and depending on the level of intellectual impairment. Only 120 residents had an International Classification of Disease (ICD) diagnosis of "mental retardation (MR)" and a valid IQ grading either by means of the Hungarian standard version of the HAWIK or by the coloured Raven test. 4 IQ groups were created: borderline (B), mild (MID), moderate (MOD) and profound (PID) intellectual disability subgroups. The Hungarian pilot version of the Behaviour Problem Inventory (BPI) was used. seventy-two percent of the residents displayed behavioural problems. All scale score means exhibited an enhancing tendency with IQ loss, as both frequency and Seventy increased linearly towards the more severe groups, but significantly only in the category of stereotyped behaviour. The authors focussed on problems of patient recruitment and discussed the measurement of behavioural and other psychiatric symptoms when researchers reported on the increased occurrence of behaviour and psychiatric symptoms in ID populations.

[A study of behaviour profile and psychiatric symptom dimensions among intellectually disabled people in residential care]. / Magatartásprofil és psichiátriai tünetdimenziók vizsgálata értelmi akadályozottsággal gondozott intézeti betegeken.

AIMS: Authors investigated the psychiatric symptoms and behaviour dimensions of people in residential care of institutions in Tolna county (South-West Hungary, Trans-Danubian region) aimed at screening the frequency of the relevant affective and behavioural symptoms associated with intellectual disability and their dependency on the level of intellectual impairment. METHODS: On the basis of HAWIK test, Hungarian standard version, 4 groups were created: subnormal, mild, moderate and profound MR subgroups. The Hungarian standard of Derogatis' Symptom Distress Checklist (SCL-90) and the validated Behaviour Problem Profile (BPI by Rojahn et al) were used. RESULTS: Towards the more profound categories, the self-injurious and stereotype behaviour are increasing, while the aggressive behaviour is most characteristic in the moderately intellectually disabled group.Concerning stereotype behaviour, both frequency and seriousness dominated in the more serious group. Although psychiatric symptoms decrease depending on the level of intellectual impairment, in 5 out of 9 dimensions, the mild intellecually impaired group has the leading role. These symptoms dimensions are: interpersonal difficulties, depression, phobic, paranoid and psychotic symptoms. CONCLUSION: Authors focus on the paramount psychiatric risks of mild intellectually disabled group (old term "debility") and emphasize the detection and treatment of the psychiatric problems.