Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report.

Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment.

Variant e19a2 BCR-ABL1 fusion transcript in typical chronic myeloid leukemia.

BACKGROUND: The landmark of chronic myeloid leukemia (CML) is the reciprocal translocation t(9;22)(q34;q11), generating the BCR-ABL1 hybrid gene. About 15 types of fusion transcripts have been described to date. Among the rarer types, e19a2 was described for the first time in 1990 by Saglio et al. (1). Here, we report on a new case of CML with the e19a2 transcript. METHODS: A 38 year-old male patient was referred for genetic investigations with a clinical diagnosis of CML. Karyotyping and molecular genetics investigations (reverse-transcription and sequencing) were performed. RESULTS: t(9;22)(q34;q11.2) was found in 100% of metaphases and the patient's BCR-ABL1 fusion gene showed the rare variant transcript e19a3 with no sequence alterations. CONCLUSIONS: CML with e19a2 fusion transcript is a rare disease with a large variety of clinical manifestations and unclear biological significance. Adding new cases to the current knowledge will contribute to the understanding of its mechanisms and the clarification of its prognosis.