Eintrag weiter verarbeiten
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia
Gespeichert in:
| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , |
| In: | Blood, 126, 2015, 23, S. 1426-1426 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine |
|---|---|
| author |
Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine |
| spellingShingle |
Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine Blood Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia Cell Biology Hematology Immunology Biochemistry |
| author_sort |
russell, lisa jane |
| spelling |
Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v126.23.1426.1426 <jats:title>Abstract</jats:title> <jats:p>Deregulated expression of the type I cytokine receptor, cytokine receptor-like factor 2 (CRLF2 -d), is observed in 5% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It occurs via three known aberrations; a cryptic reciprocal translocation with the immunoglobulin heavy chain locus (IGH); an interstitial deletion within PAR1, resulting in the P2RY8-CRLF2 fusion; rare but recurrent CRLF2 mutation (F323C). All three result in overexpression of CRLF2, however alone it is insufficient to cause overt leukaemia. Mutations of the Janus kinase (JAK) family genes and the IL7 receptor, are recurrent (50% of CRLF2-d) and together with CRLF2 -d result in transformation of mouse BaF3 cells. We noted that outcome data from different study groups were inconsistent, with patients being classified as either high or intermediate risk. Thus, in this largest study to date, our aim was to acertain whether differences in clinical and/or genetic features between patients with CRLF2-d and involvement of either IGH or P2RY8 may define them as different disease entities and partly explain the outcome heterogeneity.</jats:p> <jats:p>Among 160 CRLF2-d patients, chromosomal analysis confirmed a high incidence of additional somatic copies of chromosomes X (39/88, 44%) and 21 (23/88, 26%) and identified that aneuploidy of chromosomes 9 (5/88, 6%) and 17 (7/88, 8%) were recurrent in both groups. From comparison of patients with IGH-CRLF2 and P2RY8-CRLF2, we noted a higher frequency of IKZF1 (79% v 37% p<0.001) and BTG1 (50% v 8%, p<0.001) deletions and greater complexity (>3 additional copy number alterations (CNA)) by MLPA (SALSA MLPA P335 kit, MRC Holland, The Netherlands) (p=0.037) among IGH-CRLF2 patients. We verified that (48/160) 30% of CRLF2 -d patients were Down syndrome (DS).</jats:p> <jats:p>In addition to CNA within the immunoglobulin loci and the genes investigated by MLPA, SNP6.0 arrays (Affymetrix, Santa Clara, USA) (n=25) and subsequent FISH screening identified recurrent CNA in the histone cluster at 6p22.2 (7/25, 28%), VPREB1 (6/25, 24%), ADD3 (14/58, 24%), BTLA (4/25, 16%), SLX4IP (12/43, 28%), SERP2 and TSC22D1 (6/53, 11%), PBX3 (16/54, 30%). A novel finding was an interstitial deletion at Xp11.4 fusing USP9X to DDX3X (9/50, 18%).</jats:p> <jats:p>A total of 137 somatic structural variants (SV) were detected by whole genome sequencing of 11 patients [tandem duplication- (n=6), deletion- (n=104), inversion- (n=14) and translocation-type (n=13)] creating an average of 12.7 validated SV per patient. Mutations were identified at an incidence of 12.8 per patient, including mutations in JAK1 and JAK2 (40%) and IL7R, CACNA1D and USH2A (n=2). Mutations in kinase genes were common and unique to all patients, a number have not been previously reported (e.g. ERBB4, TTBK1 and STK38L). Of interest, 7 patients had ≥1 point mutation in gene(s) involved in cell adhesion (e.g. NPNT, ADAM29, ITGB7, COL3A1 and USH2A).</jats:p> <jats:p>There was a significant difference in the median age and white blood cell count (WBC) between P2RY8-CRLF2 and IGH-CRLF2 (4yrs v 14yrs, p<0.001 and WBC >50x106 /L - 25% v 44%, p=0.021). Overall IGH-CRLF2 patients had a worse outcome compared to P2RY8-CRLF2 (p=0.191) with outcome heterogeneity in relation to gender (IGH females, HR 3.75, p=0.003), number of CNA (IGH <3 genes deleted, HR 3.79, p=0.047) and treatment trial (IGH have worse outcome on ALL97, HR 3.15, p=0.014) being observed. There was no heterogeneity for age (p=0.458), WBC (p=0.331), cytogenetic risk (p=1.0), MRD (p=1.0) or DS-ALL (p=0.877).</jats:p> <jats:p>In summary we have confirmed differences in age and WBC, involvement of kinase gene mutations and chromosomal gains in CRLF2-d ALL. Other findings included recurrent deletions involving TSC22D1 and PBX3, transcription factors involved in other human cancers; SLX4IP, an uncharacterized gene, frequently deleted in childhood ALL; the novel involvement of USP9X, a deubiquitinase involved in cancer development. We also identified recurrent mutations in cell adhesion genes. We showed that IGH-CRLF2 patients had a worse outcome, with heterogeneity seen between gender, number of gene deletions and treatment trial. We have shown that there are genetic and clinical differences dependent on whether CRLF2 is deregulated by IGH or P2RY8, suggesting that they should be regarded as different clincial entities in future studies.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Campbell: 14M genomics: Other: Co-founder and consultant.</jats:p> </jats:sec> Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia Blood |
| doi_str_mv |
10.1182/blood.v126.23.1426.1426 |
| facet_avail |
Online Free |
| finc_class_facet |
Biologie Medizin Chemie und Pharmazie |
| format |
ElectronicArticle |
| fullrecord |
blob:ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI2LjIzLjE0MjYuMTQyNg |
| id |
ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI2LjIzLjE0MjYuMTQyNg |
| institution |
DE-Gla1 DE-Zi4 DE-15 DE-Rs1 DE-Pl11 DE-105 DE-14 DE-Ch1 DE-L229 DE-D275 DE-Bn3 DE-Brt1 DE-Zwi2 DE-D161 |
| imprint |
American Society of Hematology, 2015 |
| imprint_str_mv |
American Society of Hematology, 2015 |
| issn |
0006-4971 1528-0020 |
| issn_str_mv |
0006-4971 1528-0020 |
| language |
English |
| mega_collection |
American Society of Hematology (CrossRef) |
| match_str |
russell2015clincialandgeneticlandscapesdifferbetweenighcrlf2andp2ry8crlf2acutelymphoblasticleukaemia |
| publishDateSort |
2015 |
| publisher |
American Society of Hematology |
| recordtype |
ai |
| record_format |
ai |
| series |
Blood |
| source_id |
49 |
| title |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_unstemmed |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_full |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_fullStr |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_full_unstemmed |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_short |
Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_sort |
clincial and genetic landscapes differ between igh-crlf2 and p2ry8-crlf2 acute lymphoblastic leukaemia |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v126.23.1426.1426 |
| publishDate |
2015 |
| physical |
1426-1426 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Deregulated expression of the type I cytokine receptor, cytokine receptor-like factor 2 (CRLF2 -d), is observed in 5% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It occurs via three known aberrations; a cryptic reciprocal translocation with the immunoglobulin heavy chain locus (IGH); an interstitial deletion within PAR1, resulting in the P2RY8-CRLF2 fusion; rare but recurrent CRLF2 mutation (F323C). All three result in overexpression of CRLF2, however alone it is insufficient to cause overt leukaemia. Mutations of the Janus kinase (JAK) family genes and the IL7 receptor, are recurrent (50% of CRLF2-d) and together with CRLF2 -d result in transformation of mouse BaF3 cells. We noted that outcome data from different study groups were inconsistent, with patients being classified as either high or intermediate risk. Thus, in this largest study to date, our aim was to acertain whether differences in clinical and/or genetic features between patients with CRLF2-d and involvement of either IGH or P2RY8 may define them as different disease entities and partly explain the outcome heterogeneity.</jats:p>
<jats:p>Among 160 CRLF2-d patients, chromosomal analysis confirmed a high incidence of additional somatic copies of chromosomes X (39/88, 44%) and 21 (23/88, 26%) and identified that aneuploidy of chromosomes 9 (5/88, 6%) and 17 (7/88, 8%) were recurrent in both groups. From comparison of patients with IGH-CRLF2 and P2RY8-CRLF2, we noted a higher frequency of IKZF1 (79% v 37% p<0.001) and BTG1 (50% v 8%, p<0.001) deletions and greater complexity (>3 additional copy number alterations (CNA)) by MLPA (SALSA MLPA P335 kit, MRC Holland, The Netherlands) (p=0.037) among IGH-CRLF2 patients. We verified that (48/160) 30% of CRLF2 -d patients were Down syndrome (DS).</jats:p>
<jats:p>In addition to CNA within the immunoglobulin loci and the genes investigated by MLPA, SNP6.0 arrays (Affymetrix, Santa Clara, USA) (n=25) and subsequent FISH screening identified recurrent CNA in the histone cluster at 6p22.2 (7/25, 28%), VPREB1 (6/25, 24%), ADD3 (14/58, 24%), BTLA (4/25, 16%), SLX4IP (12/43, 28%), SERP2 and TSC22D1 (6/53, 11%), PBX3 (16/54, 30%). A novel finding was an interstitial deletion at Xp11.4 fusing USP9X to DDX3X (9/50, 18%).</jats:p>
<jats:p>A total of 137 somatic structural variants (SV) were detected by whole genome sequencing of 11 patients [tandem duplication- (n=6), deletion- (n=104), inversion- (n=14) and translocation-type (n=13)] creating an average of 12.7 validated SV per patient. Mutations were identified at an incidence of 12.8 per patient, including mutations in JAK1 and JAK2 (40%) and IL7R, CACNA1D and USH2A (n=2). Mutations in kinase genes were common and unique to all patients, a number have not been previously reported (e.g. ERBB4, TTBK1 and STK38L). Of interest, 7 patients had ≥1 point mutation in gene(s) involved in cell adhesion (e.g. NPNT, ADAM29, ITGB7, COL3A1 and USH2A).</jats:p>
<jats:p>There was a significant difference in the median age and white blood cell count (WBC) between P2RY8-CRLF2 and IGH-CRLF2 (4yrs v 14yrs, p<0.001 and WBC >50x106 /L - 25% v 44%, p=0.021). Overall IGH-CRLF2 patients had a worse outcome compared to P2RY8-CRLF2 (p=0.191) with outcome heterogeneity in relation to gender (IGH females, HR 3.75, p=0.003), number of CNA (IGH <3 genes deleted, HR 3.79, p=0.047) and treatment trial (IGH have worse outcome on ALL97, HR 3.15, p=0.014) being observed. There was no heterogeneity for age (p=0.458), WBC (p=0.331), cytogenetic risk (p=1.0), MRD (p=1.0) or DS-ALL (p=0.877).</jats:p>
<jats:p>In summary we have confirmed differences in age and WBC, involvement of kinase gene mutations and chromosomal gains in CRLF2-d ALL. Other findings included recurrent deletions involving TSC22D1 and PBX3, transcription factors involved in other human cancers; SLX4IP, an uncharacterized gene, frequently deleted in childhood ALL; the novel involvement of USP9X, a deubiquitinase involved in cancer development. We also identified recurrent mutations in cell adhesion genes. We showed that IGH-CRLF2 patients had a worse outcome, with heterogeneity seen between gender, number of gene deletions and treatment trial. We have shown that there are genetic and clinical differences dependent on whether CRLF2 is deregulated by IGH or P2RY8, suggesting that they should be regarded as different clincial entities in future studies.</jats:p>
<jats:sec>
<jats:title>Disclosures</jats:title>
<jats:p>Campbell: 14M genomics: Other: Co-founder and consultant.</jats:p>
</jats:sec> |
| container_issue |
23 |
| container_start_page |
1426 |
| container_title |
Blood |
| container_volume |
126 |
| format_de105 |
Article, E-Article |
| format_de14 |
Article, E-Article |
| format_de15 |
Article, E-Article |
| format_de520 |
Article, E-Article |
| format_de540 |
Article, E-Article |
| format_dech1 |
Article, E-Article |
| format_ded117 |
Article, E-Article |
| format_degla1 |
E-Article |
| format_del152 |
Buch |
| format_del189 |
Article, E-Article |
| format_dezi4 |
Article |
| format_dezwi2 |
Article, E-Article |
| format_finc |
Article, E-Article |
| format_nrw |
Article, E-Article |
| _version_ |
1792321469096656901 |
| geogr_code |
not assigned |
| last_indexed |
2024-03-01T11:02:30.33Z |
| geogr_code_person |
not assigned |
| openURL |
url_ver=Z39.88-2004&ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fvufind.svn.sourceforge.net%3Agenerator&rft.title=Clincial+and+Genetic+Landscapes+Differ+Between+IGH-CRLF2+and+P2RY8-CRLF2+Acute+Lymphoblastic+Leukaemia&rft.date=2015-12-03&genre=article&issn=1528-0020&volume=126&issue=23&spage=1426&epage=1426&pages=1426-1426&jtitle=Blood&atitle=Clincial+and+Genetic+Landscapes+Differ+Between+IGH-CRLF2+and+P2RY8-CRLF2+Acute+Lymphoblastic+Leukaemia&aulast=Harrison&aufirst=Christine&rft_id=info%3Adoi%2F10.1182%2Fblood.v126.23.1426.1426&rft.language%5B0%5D=eng |
| SOLR | |
| _version_ | 1792321469096656901 |
| author | Russell, Lisa Jane, Jones, Lisa, Enshaei, Amir, Rutherford, Jamie, Tonin, Stefano, Ryan, Sarra, Eswaran, Jeyanthy, Papaemmanuil, Elli, Tubio, Jose, Campbell, Peter J, Moorman, Anthony V, Harrison, Christine |
| author_facet | Russell, Lisa Jane, Jones, Lisa, Enshaei, Amir, Rutherford, Jamie, Tonin, Stefano, Ryan, Sarra, Eswaran, Jeyanthy, Papaemmanuil, Elli, Tubio, Jose, Campbell, Peter J, Moorman, Anthony V, Harrison, Christine, Russell, Lisa Jane, Jones, Lisa, Enshaei, Amir, Rutherford, Jamie, Tonin, Stefano, Ryan, Sarra, Eswaran, Jeyanthy, Papaemmanuil, Elli, Tubio, Jose, Campbell, Peter J, Moorman, Anthony V, Harrison, Christine |
| author_sort | russell, lisa jane |
| container_issue | 23 |
| container_start_page | 1426 |
| container_title | Blood |
| container_volume | 126 |
| description | <jats:title>Abstract</jats:title> <jats:p>Deregulated expression of the type I cytokine receptor, cytokine receptor-like factor 2 (CRLF2 -d), is observed in 5% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It occurs via three known aberrations; a cryptic reciprocal translocation with the immunoglobulin heavy chain locus (IGH); an interstitial deletion within PAR1, resulting in the P2RY8-CRLF2 fusion; rare but recurrent CRLF2 mutation (F323C). All three result in overexpression of CRLF2, however alone it is insufficient to cause overt leukaemia. Mutations of the Janus kinase (JAK) family genes and the IL7 receptor, are recurrent (50% of CRLF2-d) and together with CRLF2 -d result in transformation of mouse BaF3 cells. We noted that outcome data from different study groups were inconsistent, with patients being classified as either high or intermediate risk. Thus, in this largest study to date, our aim was to acertain whether differences in clinical and/or genetic features between patients with CRLF2-d and involvement of either IGH or P2RY8 may define them as different disease entities and partly explain the outcome heterogeneity.</jats:p> <jats:p>Among 160 CRLF2-d patients, chromosomal analysis confirmed a high incidence of additional somatic copies of chromosomes X (39/88, 44%) and 21 (23/88, 26%) and identified that aneuploidy of chromosomes 9 (5/88, 6%) and 17 (7/88, 8%) were recurrent in both groups. From comparison of patients with IGH-CRLF2 and P2RY8-CRLF2, we noted a higher frequency of IKZF1 (79% v 37% p<0.001) and BTG1 (50% v 8%, p<0.001) deletions and greater complexity (>3 additional copy number alterations (CNA)) by MLPA (SALSA MLPA P335 kit, MRC Holland, The Netherlands) (p=0.037) among IGH-CRLF2 patients. We verified that (48/160) 30% of CRLF2 -d patients were Down syndrome (DS).</jats:p> <jats:p>In addition to CNA within the immunoglobulin loci and the genes investigated by MLPA, SNP6.0 arrays (Affymetrix, Santa Clara, USA) (n=25) and subsequent FISH screening identified recurrent CNA in the histone cluster at 6p22.2 (7/25, 28%), VPREB1 (6/25, 24%), ADD3 (14/58, 24%), BTLA (4/25, 16%), SLX4IP (12/43, 28%), SERP2 and TSC22D1 (6/53, 11%), PBX3 (16/54, 30%). A novel finding was an interstitial deletion at Xp11.4 fusing USP9X to DDX3X (9/50, 18%).</jats:p> <jats:p>A total of 137 somatic structural variants (SV) were detected by whole genome sequencing of 11 patients [tandem duplication- (n=6), deletion- (n=104), inversion- (n=14) and translocation-type (n=13)] creating an average of 12.7 validated SV per patient. Mutations were identified at an incidence of 12.8 per patient, including mutations in JAK1 and JAK2 (40%) and IL7R, CACNA1D and USH2A (n=2). Mutations in kinase genes were common and unique to all patients, a number have not been previously reported (e.g. ERBB4, TTBK1 and STK38L). Of interest, 7 patients had ≥1 point mutation in gene(s) involved in cell adhesion (e.g. NPNT, ADAM29, ITGB7, COL3A1 and USH2A).</jats:p> <jats:p>There was a significant difference in the median age and white blood cell count (WBC) between P2RY8-CRLF2 and IGH-CRLF2 (4yrs v 14yrs, p<0.001 and WBC >50x106 /L - 25% v 44%, p=0.021). Overall IGH-CRLF2 patients had a worse outcome compared to P2RY8-CRLF2 (p=0.191) with outcome heterogeneity in relation to gender (IGH females, HR 3.75, p=0.003), number of CNA (IGH <3 genes deleted, HR 3.79, p=0.047) and treatment trial (IGH have worse outcome on ALL97, HR 3.15, p=0.014) being observed. There was no heterogeneity for age (p=0.458), WBC (p=0.331), cytogenetic risk (p=1.0), MRD (p=1.0) or DS-ALL (p=0.877).</jats:p> <jats:p>In summary we have confirmed differences in age and WBC, involvement of kinase gene mutations and chromosomal gains in CRLF2-d ALL. Other findings included recurrent deletions involving TSC22D1 and PBX3, transcription factors involved in other human cancers; SLX4IP, an uncharacterized gene, frequently deleted in childhood ALL; the novel involvement of USP9X, a deubiquitinase involved in cancer development. We also identified recurrent mutations in cell adhesion genes. We showed that IGH-CRLF2 patients had a worse outcome, with heterogeneity seen between gender, number of gene deletions and treatment trial. We have shown that there are genetic and clinical differences dependent on whether CRLF2 is deregulated by IGH or P2RY8, suggesting that they should be regarded as different clincial entities in future studies.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Campbell: 14M genomics: Other: Co-founder and consultant.</jats:p> </jats:sec> |
| doi_str_mv | 10.1182/blood.v126.23.1426.1426 |
| facet_avail | Online, Free |
| finc_class_facet | Biologie, Medizin, Chemie und Pharmazie |
| format | ElectronicArticle |
| format_de105 | Article, E-Article |
| format_de14 | Article, E-Article |
| format_de15 | Article, E-Article |
| format_de520 | Article, E-Article |
| format_de540 | Article, E-Article |
| format_dech1 | Article, E-Article |
| format_ded117 | Article, E-Article |
| format_degla1 | E-Article |
| format_del152 | Buch |
| format_del189 | Article, E-Article |
| format_dezi4 | Article |
| format_dezwi2 | Article, E-Article |
| format_finc | Article, E-Article |
| format_nrw | Article, E-Article |
| geogr_code | not assigned |
| geogr_code_person | not assigned |
| id | ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE4Mi9ibG9vZC52MTI2LjIzLjE0MjYuMTQyNg |
| imprint | American Society of Hematology, 2015 |
| imprint_str_mv | American Society of Hematology, 2015 |
| institution | DE-Gla1, DE-Zi4, DE-15, DE-Rs1, DE-Pl11, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161 |
| issn | 0006-4971, 1528-0020 |
| issn_str_mv | 0006-4971, 1528-0020 |
| language | English |
| last_indexed | 2024-03-01T11:02:30.33Z |
| match_str | russell2015clincialandgeneticlandscapesdifferbetweenighcrlf2andp2ry8crlf2acutelymphoblasticleukaemia |
| mega_collection | American Society of Hematology (CrossRef) |
| physical | 1426-1426 |
| publishDate | 2015 |
| publishDateSort | 2015 |
| publisher | American Society of Hematology |
| record_format | ai |
| recordtype | ai |
| series | Blood |
| source_id | 49 |
| spelling | Russell, Lisa Jane Jones, Lisa Enshaei, Amir Rutherford, Jamie Tonin, Stefano Ryan, Sarra Eswaran, Jeyanthy Papaemmanuil, Elli Tubio, Jose Campbell, Peter J Moorman, Anthony V Harrison, Christine 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v126.23.1426.1426 <jats:title>Abstract</jats:title> <jats:p>Deregulated expression of the type I cytokine receptor, cytokine receptor-like factor 2 (CRLF2 -d), is observed in 5% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It occurs via three known aberrations; a cryptic reciprocal translocation with the immunoglobulin heavy chain locus (IGH); an interstitial deletion within PAR1, resulting in the P2RY8-CRLF2 fusion; rare but recurrent CRLF2 mutation (F323C). All three result in overexpression of CRLF2, however alone it is insufficient to cause overt leukaemia. Mutations of the Janus kinase (JAK) family genes and the IL7 receptor, are recurrent (50% of CRLF2-d) and together with CRLF2 -d result in transformation of mouse BaF3 cells. We noted that outcome data from different study groups were inconsistent, with patients being classified as either high or intermediate risk. Thus, in this largest study to date, our aim was to acertain whether differences in clinical and/or genetic features between patients with CRLF2-d and involvement of either IGH or P2RY8 may define them as different disease entities and partly explain the outcome heterogeneity.</jats:p> <jats:p>Among 160 CRLF2-d patients, chromosomal analysis confirmed a high incidence of additional somatic copies of chromosomes X (39/88, 44%) and 21 (23/88, 26%) and identified that aneuploidy of chromosomes 9 (5/88, 6%) and 17 (7/88, 8%) were recurrent in both groups. From comparison of patients with IGH-CRLF2 and P2RY8-CRLF2, we noted a higher frequency of IKZF1 (79% v 37% p<0.001) and BTG1 (50% v 8%, p<0.001) deletions and greater complexity (>3 additional copy number alterations (CNA)) by MLPA (SALSA MLPA P335 kit, MRC Holland, The Netherlands) (p=0.037) among IGH-CRLF2 patients. We verified that (48/160) 30% of CRLF2 -d patients were Down syndrome (DS).</jats:p> <jats:p>In addition to CNA within the immunoglobulin loci and the genes investigated by MLPA, SNP6.0 arrays (Affymetrix, Santa Clara, USA) (n=25) and subsequent FISH screening identified recurrent CNA in the histone cluster at 6p22.2 (7/25, 28%), VPREB1 (6/25, 24%), ADD3 (14/58, 24%), BTLA (4/25, 16%), SLX4IP (12/43, 28%), SERP2 and TSC22D1 (6/53, 11%), PBX3 (16/54, 30%). A novel finding was an interstitial deletion at Xp11.4 fusing USP9X to DDX3X (9/50, 18%).</jats:p> <jats:p>A total of 137 somatic structural variants (SV) were detected by whole genome sequencing of 11 patients [tandem duplication- (n=6), deletion- (n=104), inversion- (n=14) and translocation-type (n=13)] creating an average of 12.7 validated SV per patient. Mutations were identified at an incidence of 12.8 per patient, including mutations in JAK1 and JAK2 (40%) and IL7R, CACNA1D and USH2A (n=2). Mutations in kinase genes were common and unique to all patients, a number have not been previously reported (e.g. ERBB4, TTBK1 and STK38L). Of interest, 7 patients had ≥1 point mutation in gene(s) involved in cell adhesion (e.g. NPNT, ADAM29, ITGB7, COL3A1 and USH2A).</jats:p> <jats:p>There was a significant difference in the median age and white blood cell count (WBC) between P2RY8-CRLF2 and IGH-CRLF2 (4yrs v 14yrs, p<0.001 and WBC >50x106 /L - 25% v 44%, p=0.021). Overall IGH-CRLF2 patients had a worse outcome compared to P2RY8-CRLF2 (p=0.191) with outcome heterogeneity in relation to gender (IGH females, HR 3.75, p=0.003), number of CNA (IGH <3 genes deleted, HR 3.79, p=0.047) and treatment trial (IGH have worse outcome on ALL97, HR 3.15, p=0.014) being observed. There was no heterogeneity for age (p=0.458), WBC (p=0.331), cytogenetic risk (p=1.0), MRD (p=1.0) or DS-ALL (p=0.877).</jats:p> <jats:p>In summary we have confirmed differences in age and WBC, involvement of kinase gene mutations and chromosomal gains in CRLF2-d ALL. Other findings included recurrent deletions involving TSC22D1 and PBX3, transcription factors involved in other human cancers; SLX4IP, an uncharacterized gene, frequently deleted in childhood ALL; the novel involvement of USP9X, a deubiquitinase involved in cancer development. We also identified recurrent mutations in cell adhesion genes. We showed that IGH-CRLF2 patients had a worse outcome, with heterogeneity seen between gender, number of gene deletions and treatment trial. We have shown that there are genetic and clinical differences dependent on whether CRLF2 is deregulated by IGH or P2RY8, suggesting that they should be regarded as different clincial entities in future studies.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Campbell: 14M genomics: Other: Co-founder and consultant.</jats:p> </jats:sec> Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia Blood |
| spellingShingle | Russell, Lisa Jane, Jones, Lisa, Enshaei, Amir, Rutherford, Jamie, Tonin, Stefano, Ryan, Sarra, Eswaran, Jeyanthy, Papaemmanuil, Elli, Tubio, Jose, Campbell, Peter J, Moorman, Anthony V, Harrison, Christine, Blood, Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia, Cell Biology, Hematology, Immunology, Biochemistry |
| title | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_full | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_fullStr | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_full_unstemmed | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_short | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| title_sort | clincial and genetic landscapes differ between igh-crlf2 and p2ry8-crlf2 acute lymphoblastic leukaemia |
| title_unstemmed | Clincial and Genetic Landscapes Differ Between IGH-CRLF2 and P2RY8-CRLF2 Acute Lymphoblastic Leukaemia |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v126.23.1426.1426 |