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Clonal hierarchy and allelic mutation segregation in a myelofibrosis patient with two distinct LNK mutations

Leukemia volume 25, pages 1056–1058 (2011)Cite this article

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Myeloproliferative neoplasms (MPN) have been associated with several mutations including those that involve JAK, MPL, TET2, IDH, CBL, IKZF1, EZH2 and LNK. None of these mutations is currently considered a disease-initiating event and previous studies have suggested the absence of mutual exclusivity amongst mutations; clonal hierarchy could not be predicted when two or more of these mutations co-exist in the same patient.1 The recent discovery of LNK mutations in JAK2V617F-negative MPN suggested an alternative mechanism of JAK-STAT (Janus kinase/signal transducers and activators of transcription) activation and clonal erythrocytosis.2, 3 However, subsequent studies showed that JAK2 and LNK mutations are not necessarily mutually exclusive and the pathogenetic contribution of LNK mutations, in the presence of JAK2V617F, remains unclear.4 We recently detected two distinct LNK mutations in each of two patients with primary myelofibrosis. One of the patients had two LNK mutations (LNK 955_delA and LNK 685-691_delGGCCCCG) and also harbored IDH2R140Q and JAK2V617F, in both chronic- and blast-phase samples. This patient had a normal karyotype. In a Mayo Clinic Institutional Review Board approved study, we conducted single colony studies to determine the clonal sub-structure in this patient and sub-cloning experiments to ascertain whether the two LNK mutations occurred on the same or different LNK alleles.

Taken together, the results of this study underscore the complexity of clonal structure and composition in MPN. Specifically, LNK mutations were shown to be acquired either early or late during the course of clonal evolution, and were not mutually exclusive of other MPN-relevant mutations. Furthermore, LNK mutations were for the first time demonstrated to involve both LNK alleles, suggesting a selective advantage for lower LNK protein levels than is seen in the simple heterozygous mutated state; in this case, two different mutations appear to have involved each LNK allele in an independent and sequential fashion. Previous studies have shown the occurrence of double JAK2 mutations in the form of both independent clones,5 and the same clone with the two mutations in cis configuration.6 The double LNK mutation in our patient were in trans and the presence of single colonies with both homozygous LNK 685-691_del GGCCCCG and heterozygous LNK 955_delA further illustrate the extent of genomic instability associated with clonal evolution; the underlying mechanism for loss-of-heterozygosity involving only one of the two LNK mutations could not be ascertained.

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References

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Acknowledgements

AP is partly supported by a grant from the Henry J Predolin Foundation. AP and AT designed the study, contributed patient samples, analyzed the data and wrote the paper. TLL conducted the experiments and wrote the paper. CF conducted experiments.

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  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    T L Lasho, A Tefferi, C Finke & A Pardanani

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  1. T L Lasho
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  2. A Tefferi
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  3. C Finke
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  4. A Pardanani
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Correspondence to A Pardanani.

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Lasho, T., Tefferi, A., Finke, C. et al. Clonal hierarchy and allelic mutation segregation in a myelofibrosis patient with two distinct LNK mutations. Leukemia 25, 1056–1058 (2011). https://doi.org/10.1038/leu.2011.45

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