Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

Mutations and prognosis in primary myelofibrosis

Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet

ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.

Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.

DNMT3A in haematological malignancies.

Purpose To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS). Patients, Materials, and Methods Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct sequencing and for expression levels of ASXL1. The prognostic impact of ASXL1 mutation and expression levels was evaluated in the context of other clinical and molecular prognostic markers. Results Mutations in ASXL1 occurred with a frequency of 20.7% in MDS (n = 40 of 193) with 70% (n = 28) of mutations being frameshift mutations and 30% (n = 12) being heterozygous point mutations leading to translational changes. ASXL1 mutations were correlated with an intermediate-risk karyotype (P = .002) but not with other clinical parameters. The presence of ASXL1 mutations was associated with a shorter overall survival for frameshift and point mutations combined (hazard ratio [HR], 1.744; 95% CI, 1.08 to 2.82; P = ....

Prognostic Significance of ASXL1 Mutations in Patients With Myelodysplastic Syndromes

Gene mutations and epigenetic changes have been shown to play significant roles in the pathogenesis of myelodysplastic syndromes. Recently, mutations in DNMT3A were identified in 22.1% of patients with acute myeloid leukemia. In this study, we analyzed the frequency and clinical impact of DNMT3A mutations in a cohort of 193 patients with myelodysplastic syndromes. Mutations in DNMT3A were found in 2.6% of patients. The majority of mutations were heterozygous missense mutations affecting codon R882. Patients with DNMT3A mutations were found to have a higher rate of transformation to acute myeloid leukemia. When assessing the global methylation levels in patients with mutated versus unmutated DNMT3A and healthy controls no difference in global DNA methylation levels between the two groups was seen. Our data show that in patients with myelodysplastic syndromes, DNMT3A mutations occur at a low frequency and may be a risk factor for leukemia progression.

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Rare occurrence of DNMT3A mutations in myelodysplastic syndromes

Noch nie waren so viele Menschen auf der Welt gleichzeitig an einer Tuberkulose erkrankt wie in der heutigen Zeit. Auch ist die Tuberkulose weiterhin die häufigste zum Tode führende bakterielle Infektionskrankheit weltweit. Die ambitionierten Ziele der Weltgesundheitsorganisation aus dem Jahr 2014, eine baldige globale Elimination der Tuberkulose zu erreichen, erscheinen nicht realistisch. Aber dem aktuellen Trend folgend, könnte die Tuberkulose bis 2040 in der EU eliminiert werden. Seit Beginn des Jahres 2022 hat es so viele Innovationen für die Behandlung der Tuberkulose gegeben, wie in keiner anderen vergleichbaren Zeitspanne zuvor. Eine effektive Therapie der latenten Tuberkulose ist nun über nur einen Monat hinweg mit Rifapentin und Isoniazid möglich, allerdings ist Rifapentin zwar in den USA, aber nicht in der EU zugelassen und muss für den Einzelfall importiert werden. Die Dauer der Standardtherapie der Tuberkulose kann auf vier Monate verkürzt werden, allerdings beruht auch dieses Therapieregime neben Isoniazid, Pyrazinamid und Moxifloxacin auf Rifapentin. Die Zulassung von Rifapentin in Europa ist somit ein dringend notwendiger Schritt, um die Therapie der Tuberkulose zu verkürzen. Mit neuen Medikamenten könnten noch kürzere Standardtherapien von nur zwei Monaten möglich sein. Die Therapie der multiresistenten/rifampicinresistenten Tuberkulose (MDR-/RR-TB) hat sich auf sechs Monate verkürzt und ist damit genau so lang, wie die in Deutschland verfügbare Standardtherapie. Mit der Kombinationstherapie aus Bedaquilin, Pretomanid, Linezolid ± Moxifloxacin wurden in Studien mit einer Behandlungsdauer von sechs Monaten ca. 90 % der betroffenen Patient:innen geheilt. Mit 19 Medikamenten in klinischer Erprobung ist zu erwarten, dass sich die Therapie der Tuberkulose in den kommenden Jahren auch weiterhin rasch verbessern wird. 

Inna Friesen

Papers

Prognostic Significance of ASXL1 Mutations in Patients With Myelodysplastic Syndromes

Rare occurrence of DNMT3A mutations in myelodysplastic syndromes

[Treatment of tuberculosis: what is new?]

Long-term treatment outcomes in multidrug-resistant tuberculosis.