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Background: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53 -mutated AML/HR-MDS is not well defined., Objectives: To define the genetic, epigenetic, and immunologic landscape of TP53- mutant and TP53 wild-type AML and HR-MDS patients., Design: Post hoc analysis of TP53- mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab., Methods: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53- mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial., Results: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53- mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53- mutant samples suggesting a novel therapeutic target., Conclusion: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53- mutant AML/HR-MDS with mono- or multihit TP53 mutation status., Trial Registration: FUSION trial (NCT02775903)., Competing Interests: AMZ received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron, and Celgene/BMS. RMS participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc.; divested equity interest in Curis Oncology. IB, ET, DLM, BF, VH, and SR are employees of Celgene, a Bristol Myers Squibb company, and may be shareholders. SH has received research funding received honoraria from FORMA Therapeutics. TH is the owner of Munich Leukemia Laboratory. All other authors have no relevant conflicts of interest to declare., (© The Author(s), 2024.)

The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein, we show that GC formation is only minimally impaired in Bcl6(+/-) or Bach2(+/-) mice, although double heterozygous Bcl6(+/-)Bach2(+/-) mice exhibit profound reduction in GC formation. Splenic B cells from Bcl6(+/-) Bach2(+/-) mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1, and CD138. Chromatin immunoprecipitation sequencing revealed that in B cells, BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6, including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation.

A fortnightly in-reach genitourinary (GU) medicine Service to a medium security male prison has been provided since April 2004. Patients are seen either by referrals from the prison general practitioner (GP), or at an individual's request. Problems have arisen due to a lack of space and time - the health adviser and doctor have to share a room. Since the prisoners have to leave Health Care by 1130 hours, if one inmate has complicated issues, it can result in these not being dealt with, or in patients not being seen as there is no flexibility. There has been an unexpectedly high DNA rate, which is multifactorial. Some prisoners have been moved to another prison since the request to be seen was made, some are on court attendances or have legal visits. Additionally some men choose not to come when sent for on the day. A few men who attend do so mistakenly, thinking that GUM is the dentist. This is particularly a problem where English is not the first language. The attendance of prisoners at the GU medicine service is noted in their prison health record, with relevant information, such as referral for management of hepatitis C. Of the 219 men seen in the first year, 55% had a GU medicine screen. The most common infections were chlamydia 10.5%, warts 12.1% and HCV 9%. The clinic has been well supported by patients and prison staff. High rates of infections are being detected and managed. The men have been happy to be screened, and despite initial concerns all are happy to provide urine specimens for chlamydia screening.

Tuberculosis is rare in Israel, especially that of the middle ear. Its rarity leads to both underdiagnosis and misdiagnosis. Since tuberculosis is treatable, diagnosis is of the utmost importance. The recent wave of immigration from countries in which tuberculosis is endemic may confront us with more cases of tuberculosis of this type.