Detection of Latent HSCs Fated to Progress to Blast Phase in Myelofibrosis Patients Several Years Before Blast Transformation

Blast phase (BP) fated clones often appear several years before blast transformation and can be traced back to hematopoietic stem cells (HSCs), according to the findings of a study presented at the 12th International Congress on Myeloproliferative Neoplasms.

Researchers studied nine myelofibrosis (MF) patients who progressed to BP and had previously aggregated chronic phase (CP) and BP samples, with an average time interval between collections between 1.5 to 6.5 years.

The time interval between CP and BP collections ranged between 1.5 to 6.6 years. In four patients, additional CP samples were available from intervening time points. Whole genome sequencing (WGS) of leukemic blasts, the MPN clone, and germline control (T-cells/buccal DNA) were performed to identify somatic mutations. The researchers detected mutations at BP in 21 ML genes with an average of 5.3 (range 2-8) genes mutated per patient. Genes that were mutated in 2 or more BP samples included SRSF2 (n=5), ASXL1 (n=4), TET2 (n=4), IDH1/2 (n=4), RUNX1 (n=4), NRAS (n=4), KRAS (n=2), U2AF1 (n=2), PHF6 (n=2), and STAG2 (n=2).

The results showed that BP-specific ML gene mutations could be detected at low frequencies in one or more cell populations several years before BP diagnosis. The study authors wrote that, “importantly, these low frequency mutations were detected within the HSC population from several patients, indicating that BP-fated clones derived from an HSC. This finding is being verified by targeted sequencing of additional BP-specific mutations identified by WGS (average of 300 variants per patient, range 37 to 659).”

The authors added that: “Identification of BP-fated clones that are latent strongly suggests that mechanisms beyond the acquisition of somatic mutations in ML genes are necessary to effectively promote full leukemic transformation.”

Ho J, et al. Detection of Latent HSCs Fated to Progress to Blast Phase in Myelofibrosis Patients Several Years Before Blast Transformation. Presented at the 12th International Congress on Myeloproliferative Neoplasms; October 24-25, 2019; New York, NY.