Genetic approaches to improve the diagnosis and management of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms and related disorders (MPN+) are a group of diseases of the blood and bone marrow characterised by clonal expansion of myeloid lineage cells. They are frequently driven by somatic abnormalities of tyrosine kinase (TK) genes, including mutations and gene fusions. Increasingly, these abnormalities are being used to diagnose, guide treatment, and monitor patient responses. This work focuses on improving current approaches to the genetic diagnosis and management of MPN+.
Initially, two patients with suspected TK rearrangements had CCDC88C::PDGFRB and RANBP2::ABL1 fusions characterised, allowing for the design of a monitoring assay for one patient, retrospectively demonstrating a significant reduction of disease during treatment. Alongside this, screening for novel mutations of JAK2 detected a recurrent exon 13 variant in several cases with eosinophilia.
Next, a pan-European study was undertaken to investigate if differences in amplification efficiency between the BCR::ABL1 e14a2 and e13a2 transcript isoforms in chronic myeloid leukaemia (CML) might partially explain observations of a faster molecular response in patients expressing e14a2 compared to those with e13a2. The data demonstrated a measurable difference in performance that could be resolved by either alternative PCR methods or taking amplification efficiency into account.
Long read nanopore sequencing to detect TK fusion genes in MPN+ was explored in patients with confirmed or suspected TK fusions. A workflow was developed using adaptive sampling which was able to successfully detect 18/18 fusions of various TK genes and identified a novel AGAP2::PDGFRB rearrangement. Finally, whole genome short read sequencing data of a cohort of 69 CML patients with optimal (n=27) or suboptimal (n=42) responses to treatment was assessed for association between the somatic mutation landscape and treatment response. Although no major differences were found, suboptimal responders were significantly more likely to carry a higher proportion of somatic copy number gains compared to optimal responders.
Together, this work provides valuable insights into how current and emerging technologies can be used to better identify and monitor patients with MPN+.

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Identifiers

ORCID for Matthew Vaughan Salmon: orcid.org/0000-0003-0647-5501

ORCID for Nick Cross: orcid.org/0000-0001-5481-2555

ORCID for William Tapper: orcid.org/0000-0002-5896-1889

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