Immunosuppressive therapy related secondary haematologic malignancy is well reported. A 52 years lady with established rheumatoid arthritis developed reactive amyloidosis. This was initially treated with colchicine and cyclophosphamide and later with chlorambucil. Ten months after stopping chlorambucil she developed pancytopenia and vitamin B12 deficient megaloblastic anaemia. The pancytopenia was refractory to vitamin B12 supplements and a repeat bone marrow confirmed myelodysplasia (FABI RAEB-T). Within three weeks of this diagnosis she evolved into acute myeloid leukaemia and expired due to refractory thrombocytopenia and uncontrolled bleeding. This case stresses the need for long term follow up of RA patients treated with alkylating agents.
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Mol Med
January 2025
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
Acute myeloid leukemia (AML) is caused by altered maturation and differentiation of myeloid blasts, as well as transcriptional/epigenetic alterations, all leading to excessive proliferation of malignant blood cells in the bone marrow. Tumor heterogeneity due to the acquisition of new somatic alterations leads to a high rate of resistance to current therapies or reduces the efficacy of hematopoietic stem cell transplantation (HSCT), thus increasing the risk of relapse and mortality. Single-cell RNA sequencing (scRNA-seq) will enable the classification of AML and guide treatment approaches by profiling patients with different facets of the same disease, stratifying risk, and identifying new potential therapeutic targets at the time of diagnosis or after treatment.
View Article and Find Full Text PDFActa Pharmacol Sin
January 2025
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification.
View Article and Find Full Text PDFBlood Cancer J
January 2025
Université de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot Opale, 31037, Toulouse, France.
GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation's impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age.
View Article and Find Full Text PDFIntroduction: The real-world safety profiles of the demethylating agents Azacitidine and Decitabine remain inadequately characterized despite their widespread clinical use. Both drugs are extensively employed for the treatment of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This study aims to evaluate their adverse event (AE) profiles by leveraging data from the U.
View Article and Find Full Text PDFJ Med Chem
January 2025
Epics Therapeutics SA, rue Adrienne Bolland 47, Gosselies 6041, Belgium.
METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-methyladenosine (mA), the most abundant modification to mRNA. The prevalence of mA and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of as an proof-of-concept compound.
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