ABSTRACT Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia1,2. We identified a family with autosomal

dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a

heterozygous single-nucleotide change in _ETV6_ (_et_s variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV.

A screen of 23 families with similar phenotypes identified 2 with _ETV6_ mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a

platelet formation and leukemia predisposition. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

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Article Open access 27 March 2025 HAPLOTYPES ANALYSIS REVEALS THE GENETIC BASIS OF TYPE I CD36 DEFICIENCY Article Open access 14 October 2024 RARE GERMLINE ALTERATIONS OF MYELOPEROXIDASE

PREDISPOSE TO MYELOID NEOPLASMS Article 27 June 2022 ACCESSION CODES PRIMARY ACCESSIONS BIOPROJECT * PRJNA276621 SEQUENCE READ ARCHIVE * SRP056053 REFERENCED ACCESSIONS NCBI REFERENCE

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α-granule biogenesis. _Blood_ 120, 5032–5040 (2012). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We are grateful to the families studied for their contribution to this

project. We are also grateful to T. Shaikh, R. Spritz and J. Murray for their insightful comments. This work was supported by the Postle Family Chair in Pediatric Cancer and Blood Disorders

(J.D.P.) and by US National Institutes of Health grants HL112311 (A.S.W.) and GM103806 (J.W.R.). W.H.A.K. was supported by operating grants from the Canadian Institutes of Health Research

(CIHR; MOP-81208 and MOP-259952). P.N. and A.S. were supported by grant GGP13082 from the Telethon Foundation. AUTHOR INFORMATION Author notes * Leila Noetzli, Richard W Lo, Walter H A Kahr,

Christopher C Porter and Jorge Di Paola: These authors contributed equally to this work. * Walter H A Kahr, Christopher C Porter and Jorge Di Paola: These authors jointly supervised this

work. AUTHORS AND AFFILIATIONS * Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, USA Leila Noetzli, Alisa B Lee-Sherick, Stephen Hunger, 

Christopher C Porter & Jorge Di Paola * Human Medical Genetics and Genomics Program, University of Colorado AMC, Aurora, Colorado, USA Leila Noetzli & Jorge Di Paola * Program in

Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Richard W Lo, Ling Li, Lily Lu, Richard Leung, Fred G Pluthero & Walter H A Kahr * Department

of Biochemistry, University of Toronto, Toronto, Ontario, Canada Richard W Lo & Walter H A Kahr * Department of Pediatrics, Children's Hospital of Michigan, Wayne State University,

Detroit, Michigan, USA Michael Callaghan & Madhvi Rajpurkar * Department of Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo

Foundation, University of Pavia, Pavia, Italy Patrizia Noris, Carlo L Balduini & Alessandro Pecci * Department of Medical Sciences, University of Trieste, Trieste, Italy Anna Savoia, 

Chiara Gnan & Daniela De Rocco * Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy Anna Savoia, Chiara Gnan & Daniela De Rocco * Department of

Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, Colorado, USA Kenneth Jones, Katherine Gowan & Arthur Gutierrez-Hartmann * Department of Internal Medicine,

Haematology/Oncology, University Hospital Brno, Brno, Czech Republic Michael Doubek * Department of Medicine, Division of Rheumatology, University of Toronto, University Health Network,

Toronto, Ontario, Canada Carolina Landolt-Marticorena * Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, Buenos Aires, Argentina Paula Heller * Department of

Medicine, University of Colorado AMC, Aurora, Colorado, USA Arthur Gutierrez-Hartmann * Department of Pathology, University of Colorado AMC, Aurora, Colorado, USA Liang Xiayuan * Department

of Internal Medicine, University of Utah, Salt Lake City, Utah, USA Jesse W Rowley & Andrew S Weyrich * Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA Jesse W

Rowley & Andrew S Weyrich * Department of Paediatrics, Division of Haematology/Oncology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada Walter H A

Kahr Authors * Leila Noetzli View author publications You can also search for this author inPubMed Google Scholar * Richard W Lo View author publications You can also search for this author

inPubMed Google Scholar * Alisa B Lee-Sherick View author publications You can also search for this author inPubMed Google Scholar * Michael Callaghan View author publications You can also

search for this author inPubMed Google Scholar * Patrizia Noris View author publications You can also search for this author inPubMed Google Scholar * Anna Savoia View author publications

You can also search for this author inPubMed Google Scholar * Madhvi Rajpurkar View author publications You can also search for this author inPubMed Google Scholar * Kenneth Jones View

author publications You can also search for this author inPubMed Google Scholar * Katherine Gowan View author publications You can also search for this author inPubMed Google Scholar * Carlo

L Balduini View author publications You can also search for this author inPubMed Google Scholar * Alessandro Pecci View author publications You can also search for this author inPubMed 

Google Scholar * Chiara Gnan View author publications You can also search for this author inPubMed Google Scholar * Daniela De Rocco View author publications You can also search for this

author inPubMed Google Scholar * Michael Doubek View author publications You can also search for this author inPubMed Google Scholar * Ling Li View author publications You can also search

for this author inPubMed Google Scholar * Lily Lu View author publications You can also search for this author inPubMed Google Scholar * Richard Leung View author publications You can also

search for this author inPubMed Google Scholar * Carolina Landolt-Marticorena View author publications You can also search for this author inPubMed Google Scholar * Stephen Hunger View

author publications You can also search for this author inPubMed Google Scholar * Paula Heller View author publications You can also search for this author inPubMed Google Scholar * Arthur

Gutierrez-Hartmann View author publications You can also search for this author inPubMed Google Scholar * Liang Xiayuan View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Andrew S Weyrich View author publications You can also search for this author inPubMed Google Scholar * Walter H A Kahr View author publications You can also

search for this author inPubMed Google Scholar * Christopher C Porter View author publications You can also search for this author inPubMed Google Scholar * Jorge Di Paola View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS L.N., R.W.L., A.B.L.-S., A.S.W., W.H.A.K., C.C.P. and J.D.P. conceived and designed the experiments.

L.N., R.W.L., A.B.L.-S., R.L., F.G.P., L. Li, L. Lu, A.S., C.G. and D.D.R. performed experiments and provided critical data. M.C., M.R., P.N., C.L.B., A.P., M.D., A.G.-H., L.X. and C.L.-M.

provided patient samples and study materials, and collected and assembled data. S.H., P.H. and A.G.-H. analyzed data. K.J., K.G. and J.W.R. analyzed genomic and transcriptome data. L.N.,

R.W.L., A.B.L.-S., F.G.P., A.S.W., W.H.A.K., C.C.P. and J.D.P. wrote the manuscript. All authors reviewed and contributed to the final version of the manuscript. A.S.W., W.H.A.K., C.C.P. and

J.D.P. jointly supervised the research. CORRESPONDING AUTHORS Correspondence to Walter H A Kahr, Christopher C Porter or Jorge Di Paola. ETHICS DECLARATIONS COMPETING INTERESTS The authors

declare no competing financial interests. INTEGRATED SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 PLATELETS FROM AFFECTED PATIENTS ARE COMPARABLE TO CONTROLS ON ELECTRON MICROGRAPH.

Thin-section transmission electron micrographs of representative platelets from a normal control (A) and an affected patient (B). The ultrastructure of patient-derived platelets is

comparable to that of control cells, with occasional elongated α-granules seen in the former. Scale bars, 500 nm. SUPPLEMENTARY FIGURE 2 THE C.1252A>G CHANGE IS A SPLICE-SITE MUTATION.

RT-PCR of the transcript encoded by exons 6–8 of _ETV6_ for individuals I-2 and II-3 of family 3 with the c.1252A>G mutation. (A) Two transcripts are visible in the gel when this region

is amplified: the expected 386-bp transcript as seen in the unaffected control (C+) and a smaller, 285-bp transcript, which by reverse sequencing, demonstrate skipping of exon 7 and a peak

for a G substitution, indicating leakage of the missense mutation (B,C). (D) The sequence of the cloned product confirms the presence of the G nucleotide in exon 7. SUPPLEMENTARY FIGURE 3

IMMUNOBLOTS OF ETV6 PROTEIN EXPRESSION IN TRANSFECTED HEK293T CELLS. Plasmids containing DDK-tagged cDNA encoding either WT, p.P214L, p.R418G (missense mutation acquired by c.1252A>G) or

p.385_418del (deletion mutation acquired by c.1252A>G) _ETV6_ were transiently transfected into HEK293T cells. Whole-cell lysates were separated by 7.5% SDS-PAGE and probed with an

anti-DDK antibody. Blots show equal expression of WT (lane 1), p.P214L (lane 2), p.R418G (lane 3) and p.385_418del (lane 4). A smaller protein is seen when p.385_418del is expressed.

SUPPLEMENTARY FIGURE 4 IMMUNOBLOT ANALYSIS OF ETV6 PROTEIN CONTENT IN PATIENT-DERIVED AND CONTROL PLATELETS. Reduced whole-cell lysates from the equivalent of 107 platelets were loaded in

each lane, with equal loading confirmed by probing for GAPDH. Subjects were as described in the Figure 1 pedigrees with the addition of two unrelated normal controls. ETV6 protein size and

platelet levels were similar for affected individuals (family 1, II-1 and III-1; family 3, I-2 and II-3), an unaffected relative (family 1, III-2) and controls. SUPPLEMENTARY FIGURE 5

DIMERIZATION OF MUTANTS WITH WT ETV6. Cell lysates of HEK293T cells transfected with WT _ETV6_-Myc/DDK or WT _ETV6_-His alone or cotransfected with WT _ETV6_-His in addition to

Myc/DDK-tagged WT _ETV6_, c.641C>T (p.P214L) _ETV6_, c.1252A>G (p.R418G) _ETV6_ or c.1153_1253del (p.385_418del) _ETV6_ were incubated with anti-Myc antibody–conjugated beads, and

protein complexes were isolated. Eluate was probed for DDK (top) and His (bottom). Lanes 1 and 2 show that WT ETV6-Myc/DDK was pulled down by the beads, but WT ETV6-His was not.

Cotransfection experiments (lanes 3–6) show that both the indicated Myc/DDK-tagged protein and the His-tagged WT ETV6 protein were pulled down, indicating that the WT ETV6-His protein was

complexed with the corresponding Myc/DDK-tagged protein and that dimerization occurred. SUPPLEMENTARY FIGURE 6 SUBCELLULAR DISTRIBUTION OF PROTEIN PRODUCED BY TRANSDUCED WILD-TYPE AND MUTANT

_ETV6_ ALLELES IN MATURING (>15-ΜM) DAY 12 CULTURED MEGAKARYOCYTES. Protein produced by transduced alleles was detected via staining for Myc tag (green), while size and stage were

determined from nuclear morphology (DNA, blue) and staining for megakaryocyte-specific Von Willebrand factor (VWF, red) and CD61 (magenta). Transduced cells showed differing subcellular

distribution patterns of Myc-tagged ETV6, with ETV6P214L and ETV6R418G showing a largely cytoplasmic distribution, in contrast to the nuclear localization observed for ETV6WT. Confocal _z_

sections; scale bars, 5 μm. SUPPLEMENTARY FIGURE 7 TRANSCRIPTIONAL CHANGES INDUCED BY MUTANT ETV6. (A) Relationship of RNA-seq transcript profiles in platelets between two affected

individuals (P214L mutation), two unaffected relatives and three unrelated controls. Shown is the sample-to-sample distance matrix, with hierarchical clustering using rlog-transformed read

counts, of 15,865 detected transcripts. (B) Hierarchical clustering and heat map analysis of the relative expression of 351 transcripts involved in platelet biogenesis or function.

Expression values are DESeq2 normalized and rlog transformed. SUPPLEMENTARY FIGURE 8 HEAT MAP ANALYSIS OF THE RELATIVE EXPRESSION OF 351 TRANSCRIPTS INVOLVED IN PLATELET BIOGENESIS OR

FUNCTION. Heat map showing higher-resolution hierarchical clustering of all transcripts associated with platelet function or platelet biogenesis. Expression values are DESeq2 normalized and

rlog transformed. This list of transcripts was curated from the Reactome, and Gene Ontology databases and from transcripts enriched in platelets compared to all other tissues in Illumina’s

Human Body Map 2.0. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Note. (PDF 630 kb) SUPPLEMENTARY VIDEO

1 The nuclear concentration of ETV6 observed for endogenously expressed protein (control, non-transduced megakaryocyte). Three-dimensional volume renders (maximum intensity) prepared from

confocal laser fluorescence microscopy _z_ sections of representative day 12 cultured megakaryocytes stained for ETV6 (green), DNA (blue) and tubulin (magenta) via Imaris 7.6. (MOV 5669 kb)

SUPPLEMENTARY VIDEO 2 Nuclear concentration of ETV6 is also seen in a cell transduced with wild-type ETV6. Three-dimensional volume renders (maximum intensity) prepared from confocal laser

fluorescence microscopy _z_ sections of representative day 12 cultured megakaryocytes stained for ETV6 (green), DNA (blue) and tubulin (magenta) via Imaris 7.6. (MOV 3554 kb) SUPPLEMENTARY

VIDEO 3 Cells expressing ETV6 P214L show extensive cytoplasmic ETV6 staining. Three-dimensional volume renders (maximum intensity) prepared from confocal laser fluorescence microscopy _z_

sections of representative day 12 cultured megakaryocytes stained for ETV6 (green), DNA (blue) and tubulin (magenta) via Imaris 7.6. (MOV 7364 kb) SUPPLEMENTARY VIDEO 4 Cells expressing ETV6

R418G show extensive cytoplasmic ETV6 staining. Three-dimensional volume renders (maximum intensity) prepared from confocal laser fluorescence microscopy _z_ sections of representative day

12 cultured megakaryocytes stained for ETV6 (green), DNA (blue) and tubulin (magenta) via Imaris 7.6. (MOV 4899 kb) SUPPLEMENTARY DATA SET List of 351 platelet-specific transcripts. (XLSX 79

kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Noetzli, L., Lo, R., Lee-Sherick, A. _et al._ Germline mutations in _ETV6_ are associated with

thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. _Nat Genet_ 47, 535–538 (2015). https://doi.org/10.1038/ng.3253 Download citation * Received: 28 October

2014 * Accepted: 25 February 2015 * Published: 25 March 2015 * Issue Date: May 2015 * DOI: https://doi.org/10.1038/ng.3253 SHARE THIS ARTICLE Anyone you share the following link with will

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