The University of Southampton
University of Southampton Institutional Repository

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

PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age related clonal hermatopoiesis and myeloid neoplasia
PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age related clonal hermatopoiesis and myeloid neoplasia
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, 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.
0887-6924
1184-1194
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Pellagatti, Andrea
5cb0bcf6-cbf6-4fb9-91e0-8cc6fbd37b8f
Singh, Shalini
bea5dba2-1321-4739-8581-23af90f1eeea
Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Lin, Feng
9067ee54-a57f-4432-b390-ec81fd8aa73c
Hoade, Yvette M.
d90fc040-c7d2-442c-9bf8-3a534e5fa910
Bryant, Catherine
d53ab6c9-909d-43cb-84fc-3e197df377f3
Trim, Nicola
77f3307f-11ab-4d92-90da-d6d973ada43a
Yip, Bon Ham
c8a1ad4d-de76-4669-9f1f-9e24b3fe0422
Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Rasi, Chiara
f45f431b-2cb4-449b-af50-0cac6b251920
Forsberg, Lars A.
e67f1044-f7b9-47e1-bbc6-fc23a17c4387
Dumanski, Jan P.
b251fb79-9503-4363-bd8c-60143dd39a2c
Boultwood, Jacqueline
653d33fa-0c0a-4a8a-b119-57a6e466b334
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Pellagatti, Andrea
5cb0bcf6-cbf6-4fb9-91e0-8cc6fbd37b8f
Singh, Shalini
bea5dba2-1321-4739-8581-23af90f1eeea
Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Lin, Feng
9067ee54-a57f-4432-b390-ec81fd8aa73c
Hoade, Yvette M.
d90fc040-c7d2-442c-9bf8-3a534e5fa910
Bryant, Catherine
d53ab6c9-909d-43cb-84fc-3e197df377f3
Trim, Nicola
77f3307f-11ab-4d92-90da-d6d973ada43a
Yip, Bon Ham
c8a1ad4d-de76-4669-9f1f-9e24b3fe0422
Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Rasi, Chiara
f45f431b-2cb4-449b-af50-0cac6b251920
Forsberg, Lars A.
e67f1044-f7b9-47e1-bbc6-fc23a17c4387
Dumanski, Jan P.
b251fb79-9503-4363-bd8c-60143dd39a2c
Boultwood, Jacqueline
653d33fa-0c0a-4a8a-b119-57a6e466b334
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4

Chase, Andrew, Pellagatti, Andrea, Singh, Shalini, Score, Joannah, Tapper, William J., Lin, Feng, Hoade, Yvette M., Bryant, Catherine, Trim, Nicola, Yip, Bon Ham, Zoi, Katerina, Rasi, Chiara, Forsberg, Lars A., Dumanski, Jan P., Boultwood, Jacqueline and Cross, Nicholas C.P. (2019) PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age related clonal hermatopoiesis and myeloid neoplasia. Leukemia, 33 (5), 1184-1194. (doi:10.1038/s41375-018-0340-5).

Record type: Article

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, 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.

Text
31739_0_merged_1538387913 - Accepted Manuscript
Download (4MB)

More information

Accepted/In Press date: 3 October 2018
e-pub ahead of print date: 20 December 2018
Published date: 1 May 2019

Identifiers

Local EPrints ID: 427203
URI: http://eprints.soton.ac.uk/id/eprint/427203
ISSN: 0887-6924
PURE UUID: a05dcd0b-e17a-47b6-b3fd-a855dc1936b9
ORCID for Andrew Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for William J. Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 07 Jan 2019 17:30
Last modified: 29 Oct 2023 06:06

Export record

Altmetrics

Contributors

Author: Andrew Chase ORCID iD
Author: Andrea Pellagatti
Author: Shalini Singh
Author: Joannah Score
Author: Feng Lin
Author: Yvette M. Hoade
Author: Catherine Bryant
Author: Nicola Trim
Author: Bon Ham Yip
Author: Katerina Zoi
Author: Chiara Rasi
Author: Lars A. Forsberg
Author: Jan P. Dumanski
Author: Jacqueline Boultwood

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×