Acute Myeloid Leukemia (AML) with a single trisomy show particular clinical, morphological, genomic, and immunophenotypic features. Trisomy 4 was first described in 1986 as the sole chromosomal abnormality in AML. However, due to its rarity (< 1%), there are not enough data concerning its clinical impact. Here we report clinical, cyto-molecular, and genomic data of a young adult with AML and a rare trisomy 4 associated with a novel RUNX1 pathogenic mutation.

A 19-year-old man was referred to Hospital dos Servidores do Estado, Rio de Janeiro, Brazil. He presented a history of 30 days of anemia, fever, weight loss, thrombocytopenia, and mucocutaneous bleeding. Physical examination revealed hepatomegaly (15 cm) and splenomegaly (14 cm). Laboratory data included hemoglobin level of 6.9 g/dL, WBC of 350 × 109/L, and platelet count of 8 × 109/L. The LDH was 1650 U/L. Flow cytometry analysis revealed 83.4% of blasts showing myeloid morphology that expressed CD34, CD117, CD13, CD7, CD38, and HLA-DR, compatible with FAB AML-M0 with minimal differentiation/undifferentiated. The patient was treated under a high-risk AML protocol. On day 14 of treatment, he developed visceral septicemia and died due to septic shock. We performed G-banding and FISH experiments. NGS was performed on a targeted approach.

G-Banding revealed the karyotype 47,XY,+4. FISH with a centromeric probe for chromosome 4 confirmed trisomy 4. Molecular biology tests were positive for FLT3/ITD and negative for NPM1 mutations. NGS results revealed a novel RUNX1 missense pathogenic mutation.

Trisomy 4 is a rare chromosomal abnormality in AML, accounting for 1 < % of cases. Although its prognostic relevance has been a frequent topic of discussion in the literature, its relation to prognosis remains to be elucidated. Chilton and coworkers (2016) described 35 patients with trisomy 4 as an isolated abnormality and observed only two patients (6%) in the 16‒25 age group. Patients with trisomy 4 have a poor prognosis when associated with mutations in KIT, mapped at position 4q12, which may influence the role of trisomy 4 in leukemogenesis. The patient in the present study belongs to the same age group as the patients in the abovementioned study. However, to our knowledge, it is the first case with trisomy 4 as a sole abnormality presenting FAB AML-M0. Our patient had a poor prognosis, including hyperleukocytosis. In addition, we characterized a missense RUNX1 mutation not yet described in the literature. RUNX1 is a transcription factor part of a complex that provides stability to the RUNX1 protein, which plays a pivotal role in generating hematopoietic stem cells and their differentiation. Loss of RUNX1 function has been shown to impair cell differentiation, often resulting in leukemogenesis. Besides, RUNX1 mutations are known to cause thrombocytopenia and familial platelet disorder.

Here we present a rare AML-M0 case with trisomy 4 as a sole abnormality and highlight its association with a novel RUNX1 mutation. Although, the prognostic implications remain to be elucidated. In particular, when to consider stem cell transplantation as curative therapy of choice in RUNX1 mutated individuals to maximize benefit and minimize risk.