Chronic myeloproliferative neoplasms

PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia

Abstract

Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1–6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Score J, Cross NC. Acquired uniparental disomy in myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012;26:981–91.

  2. 2.

    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.

  3. 3.

    Raghavan M, Smith LL, Lillington DM, Chaplin T, Kakkas I, Molloy G, et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood. 2008;112:814–21.

  4. 4.

    Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113:6182–92.

  5. 5.

    Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.

  6. 6.

    Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904–8.

  7. 7.

    Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–42.

  8. 8.

    Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.

  9. 9.

    Tapper W, Jones AV, Kralovics R, Harutyunyan AS, Zoi K, Leung W, et al. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nat Commun. 2015;6:6691.

  10. 10.

    Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266–79.

  11. 11.

    Chase A, Leung W, Tapper W, Jones AV, Knoops L, Rasi C, et al. Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus. Leukemia. 2015;29:2069–74.

  12. 12.

    Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44:642–50.

  13. 13.

    Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012;44:651–8.

  14. 14.

    Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G, et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat Genet. 2014;46:624–8.

  15. 15.

    Forsberg LA, Gisselsson D, Dumanski JP. Mosaicism in health and disease - clones picking up speed. Nat Rev Genet. 2017;18:128–42.

  16. 16.

    Shlush LI. Age-related clonal hematopoiesis. Blood. 2018;131:496–504.

  17. 17.

    Gondek LP, Dunbar AJ, Szpurka H, McDevitt MA, Maciejewski JP. SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD. PLoS ONE. 2007;2:e1225.

  18. 18.

    Tapper WJ, Foulds N, Cross NC, Aranaz P, Score J, Hidalgo-Curtis C, et al. Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations. PLoS ONE. 2014;9:e86940.

  19. 19.

    Davies C, Yip BH, Fernandez-Mercado M, Woll PS, Agirre X, Prosper F, et al. Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34(+) progenitor cells. Br J Haematol. 2013;160:842–50.

  20. 20.

    Yip BH, Steeples V, Repapi E, Armstrong RN, Llorian M, Roy S, et al. The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. J Clin Invest. 2017;127:2206–21.

  21. 21.

    Picelli S, Faridani OR, Bjorklund AK, Winberg G, Sagasser S, Sandberg R. Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014;9:171–81.

  22. 22.

    Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.

  23. 23.

    Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

  24. 24.

    Liao Y, Smyth GK, Shi W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41:e108.

  25. 25.

    Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

  26. 26.

    Xiong Q, Mukherjee S, Furey TS. GSAASeqSP: a toolset for gene set association analysis of RNA-Seq data. Sci Rep. 2014;4:6347.

  27. 27.

    Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428–36.

  28. 28.

    Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27. quiz 3699

  29. 29.

    Dietrich BH, Moore J, Kyba M, dosSantos G, McCloskey F, Milne TA, et al. Tantalus, a novel ASX-interacting protein with tissue-specific functions. Dev Biol. 2001;234:441–53.

  30. 30.

    Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH. Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007;282:5101–5.

  31. 31.

    Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, et al. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015;163:712–23.

  32. 32.

    Naranbhai V, Fairfax BP, Makino S, Humburg P, Wong D, Ng E, et al. Genomic modulators of gene expression in human neutrophils. Nat Commun. 2015;6:7545.

  33. 33.

    Gren ST, Rasmussen TB, Janciauskiene S, Hakansson K, Gerwien JG, Grip O. A Single-cell gene-expression profile reveals inter-cellular heterogeneity within human monocyte subsets. PLoS ONE. 2015;10:e0144351.

  34. 34.

    Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007;178:245–55.

  35. 35.

    Knust E. G protein signaling and asymmetric cell division. Cell. 2001;107:125–8.

  36. 36.

    Huang Z, Ma L, Wang Y, Pan Z, Ren J, Liu Z, et al. MiCroKiTS 4.0: a database of midbody, centrosome, kinetochore, telomere and spindle. Nucleic Acids Res. 2015;43:D328–34.

  37. 37.

    Poleshko A, Mansfield KM, Burlingame CC, Andrake MD, Shah NR, Katz RA. The human protein PRR14 tethers heterochromatin to the nuclear lamina during interphase and mitotic exit. Cell Rep. 2013;5:292–301.

  38. 38.

    Yang M, Lewinska M, Fan X, Zhu J, Yuan ZM. PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis. Oncogene. 2016;35:5527–38.

  39. 39.

    Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ, et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia. 2010;24:1062–5.

  40. 40.

    Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013;210:2641–59.

  41. 41.

    LaFave LM, Beguelin W, Koche R, Teater M, Spitzer B, Chramiec A, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21:1344–9.

  42. 42.

    Cho YS, Kim EJ, Park UH, Sin HS, Um SJ. Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor. J Biol Chem. 2006;281:17588–98.

  43. 43.

    Park UH, Seong MR, Kim EJ, Hur W, Kim SW, Yoon SK, et al. Reciprocal regulation of LXRalpha activity by ASXL1 and ASXL2 in lipogenesis. Biochem Biophys Res Commun. 2014;443:489–94.

  44. 44.

    Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276:37731–4.

  45. 45.

    de The H, Pandolfi PP, Chen Z. Acute Promyelocytic Leukemia: A paradigm for oncoprotein-targeted cure. Cancer Cell. 2017;32:552–60.

  46. 46.

    Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R, et al. High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia. 2010;24:1139–45.

  47. 47.

    Olson EN, Nordheim A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol. 2010;11:353–65.

  48. 48.

    Record J, Malinova D, Zenner HL, Plagnol V, Nowak K, Syed F, et al. Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1. Blood. 2015;126:1527–35.

  49. 49.

    Steigemann P, Gerlich DW. Cytokinetic abscission: cellular dynamics at the midbody. Trends Cell Biol. 2009;19:606–16.

  50. 50.

    Zheng Y, Guo J, Li X, Xie Y, Hou M, Fu X, et al. An integrated overview of spatiotemporal organization and regulation in mitosis in terms of the proteins in the functional supercomplexes. Front Microbiol. 2014;5:573.

  51. 51.

    Dionne LK, Wang XJ, Prekeris R. Midbody: from cellular junk to regulator of cell polarity and cell fate. Curr Opin Cell Biol. 2015;35:51–8.

Download references

Acknowledgements

This work was funded by Bloodwise Specialist Programme Grants 13002 to NCPC, AC and WT, and 13042 to JB and AP. We are grateful to the Central England Haemato-Oncology Research Biobank for providing DNA from case D14.31916.

Author information

Correspondence to Nicholas C. P. Cross.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary material

Supplementary Table 1

Supplementary Table 4

Supplementary Table 8

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading