HNRNPC-RARA Fusion Gene in a Case with Acute Promyelocytic Leukemia Lacking PML-RARA Rearrangement Presenting with Abundant Hemophagocytosis

Abstract

A 41-year-old Chinese man was admitted to our hospital with pancytopenia in May 2020. A bone marrow (BM) smear showed hypercellularity with 83% hypergranular promyelocytes with azurophilic granules and Auer rods (Figure 1A). Furthermore, an increased number of macrophages with marked hemophagocytosis was seen (Figure 1B). Flow cytometry revealed blast cells positive for CD33, CD13, CD117, CD123, CD9, MPO, and weak CD56, but the results were negative for CD34, CD38, HLA-DR, and Tor B-cell markers. Coagulation screening showed low fibrinogen and elevated D-dimer. Screening results for the Epstein-Barr virus, cytomegalovirus, and Mycoplasma were negative. Although abundant hemophagocytosis was present, the levels of triglycerides, serum ferritin, NK cell activity, and soluble CD25 did not support the diagnosis of hemophagocytic syndrome. Reverse-transcription polymerase chain reaction analysis of the BM was negative for PML-RARA, NPM-RARA, NuMA-RARA, FIPIL-RARA, PLZF-RARA, PPK-RARA, and STAT5b-RARAWRE. The patient was resistant to all-trans retinoic acid and arsenic trioxide induction and he died of cerebral hemorrhage on day 79. Whole-transcriptome RNA sequencing analysis with an Illumina HiSeq X device (Kindstar Global, Chengdu, China) detected only two novel types of RARA-related fusion transcripts categorized as Homo sapiens heterogeneous nuclear ribonucleoprotein C (HNRNPC). Expected bands of approximately 300 bp (HNRNPC-RARA) and 270 bp (RARA-HNRNPC) were detected and the Sanger sequencing results also confirmed the existence of these two fusion transcriptions (Figure 2A).