View source for HAEM4:B-Lymphoblastic Leukemia/Lymphoma with dic(9;12)(p13;p13); PAX5/ETV6

{{DISPLAYTITLE:B-Lymphoblastic Leukemia/Lymphoma with dic(9;12)(p13;p13); PAX5/ETV6}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
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==Primary Author(s)*==
Celeste Eno, PhD, Cedars-Sinai Medical Center 
==Cancer Category/Type==
B-Lymphoblastic Leukemia
==Cancer Sub-Classification / Subtype==
B-Lymphoblastic leukemia/lymphoma with dic(9;12)(p13;p13)
==Definition / Description of Disease==
B-lymphoblastic leukemia / lymphoma ( B-ALL / LBL ) with dic(9;12) is a neoplasm of lymphoblasts committed to the B-cell lineage in which the blasts harbor a translocation between ''PAX5'' on chromosome 9 and ''ETV6'' (formerly known as ''TEL'') on chromosome 12.<ref name=":0">{{Cite journal|last=Strehl|first=S.|last2=König|first2=M.|last3=Dworzak|first3=M. N.|last4=Kalwak|first4=K.|last5=Haas|first5=O. A.|date=2003-06|title=PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13)|url=https://pubmed.ncbi.nlm.nih.gov/12764378|journal=Leukemia|volume=17|issue=6|pages=1121–1123|doi=10.1038/sj.leu.2402923|issn=0887-6924|pmid=12764378}}</ref>
==Synonyms / Terminology==
''PAX5/ETV6''; ''PAX/TEL'';  dic(9;12)(p13;p13)
==Epidemiology / Prevalence==
dic(9;12) occurs predominantly in B-progenitor ALL of childhood and young adults (age range, 1-47 years, median 12 years) but not of infancy.<ref name=":1">{{Cite journal|last=Behrendt|first=H.|last2=Charrin|first2=C.|last3=Gibbons|first3=B.|last4=Harrison|first4=C. J.|last5=Hawkins|first5=J. M.|last6=Heerema|first6=N. A.|last7=Horschler-Bötel|first7=B.|last8=Huret|first8=J. L.|last9=Laï|first9=J. L.|date=1995-01-XX|title=Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group|url=https://pubmed.ncbi.nlm.nih.gov/7845002|journal=Leukemia|volume=9|issue=1|pages=102–106|issn=0887-6924|pmid=7845002}}</ref> The dicentric translocation dic(9;12) is a recurrent chromosome abnormality that accounts for close to 1% of childhood acute lymphoblastic leukemia (ALL).<ref name=":0" />
==Clinical Features==
Clinical characteristics were similar to those of the general population of children with ALL.<ref name=":2">{{Cite journal|last=Mahmoud|first=H.|last2=Carroll|first2=A. J.|last3=Behm|first3=F.|last4=Raimondi|first4=S. C.|last5=Schuster|first5=J.|last6=Borowitz|first6=M.|last7=Land|first7=V.|last8=Pullen|first8=D. J.|last9=Vietti|first9=T. J.|date=1992-07-XX|title=The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis|url=https://pubmed.ncbi.nlm.nih.gov/1625489|journal=Leukemia|volume=6|issue=7|pages=703–707|issn=0887-6924|pmid=1625489}}</ref> One or more adverse clinical features, age > 10 years, WBC > 100 x 10(9)/l, pre-B immunophenotype, platelets < 100 x 10(9)/l, were found in over 90% of cases.<ref name=":1" />
{| class="wikitable"
|'''Signs and  Symptoms'''
|B-symptoms typical of children with ALL<ref name=":2" /> (weight loss, fever, night sweats)
|-
|'''Laboratory  Findings'''
|Adverse findings in over 90%<ref name=":1" />:

WBC > 100 x 10(9)/l

pre-B immunophenotype

platelets < 100 x 10(9)/l
|}

==Sites of Involvement==
Bone marrow and peripheral blood; Patients can present with moderate organomegaly 
==Morphologic Features==
Put your text here
==Immunophenotype==
The vast majority of leukemias with dic(9;12) is associated with a B-progenitor cell phenotype and belongs to the FAB L1 morphologic subtype. The blast cells express HLA-DR, CD10, CD19, CD24, and frequently also CD20 or CD22.<ref name=":2" /> 
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||HLA-DR, CD10, CD19, CD24
|-
|Positive (subset)||CD20 or CD22
|-
|Negative (universal)||
|-
|Negative (subset)||
|}
==Chromosomal Rearrangements (Gene Fusions)==
dic(9;12) creates the chimeric fusion between ''PAX5'' and ''ETV6''. The breakpoints in ''PAX5'' are intron 4 and in ''ETV6'' is intron 2.
{| class="wikitable"
|'''Chromosomal Rearrangement'''
|'''Genes in Fusion'''

'''(5’ or 3’ Segments)'''
|'''Pathogenic Derivative'''
|'''Prevalence'''
|'''Diagnostic  Significance (Yes, No or Unknown)'''
|'''Prognostic  Significance (Yes, No or Unknown)'''
|'''Therapeutic  Significance (Yes, No or Unknown)'''
|'''Notes'''
|-
|dic(9;12)(p13;p13)
|5' ''PAX5'' / 3' ''ETV6''
|
|1% (pediatric ALL)
|Yes
|No
|Yes
|Bone marrow transplantation is not recommended as the dic(9;12) in ALL is associated with an excellent prognosis<ref name=":2" />.
|}
==Characteristic Chromosomal Aberrations / Patterns==
[[File:Dic(9;12).jpg|thumb|Ideogram of dic(9;12)<ref>{{Cite journal|last=Hiller|first=B.|last2=Bradtke|first2=J.|last3=Balz|first3=H.|last4=Rieder|first4=H.|date=2004-11-16|title=CyDAS: a cytogenetic data analysis system|url=http://dx.doi.org/10.1093/bioinformatics/bti146|journal=Bioinformatics|volume=21|issue=7|pages=1282–1283|doi=10.1093/bioinformatics/bti146|issn=1367-4803}}</ref>]]
<br />
{| class="wikitable"
|'''Chromosomal  Pattern'''
|'''Diagnostic  Significance (Yes, No or Unknown)'''
|'''Prognostic  Significance'''

'''(Yes, No  or Unknown)'''
|'''Therapeutic  Significance'''

'''(Yes, No  or Unknown)'''
|'''Notes'''
|-
|dic(9;12)<ref name=":1" />
|Yes
|Yes
|No
|A COG study revealed the presence of a cryptic t(12;21) fusion in patients harboring dic(9;12) [inferred ISCN: der(9;12)t(9;21)(p12;q22)t(12;21)(p13;q22)] suggesting that molecular analysis should be performed to determine whether the dicentric chromosome results in ''PAX5/ETV6'' fusion or whether the case has ''ETV6/RUNX1'' fusion<ref name=":3">{{Cite journal|last=Gastier-Foster|first=Julie M.|last2=Carroll|first2=Andrew J.|last3=Ell|first3=Denise|last4=Harvey|first4=Richard|last5=Chen|first5=I-Ming|last6=Ketterling|first6=Rhett|last7=Meloni-Ehrig|first7=Aurelia|last8=Opheim|first8=Kent E.|last9=Patil|first9=Shivanand|date=2007-11-16|title=Two Distinct Subsets of dic(9;12)(p12;p11.2) among Children with B-Cell Precursor Acute Lymphoblastic Leukemia (ALL): PAX5-ETV6 and ETV6-RUNX1 Rearrangements: A Report from the Children’s Oncology Group.|url=https://doi.org/10.1182/blood.V110.11.1439.1439|journal=Blood|volume=110|issue=11|pages=1439–1439|doi=10.1182/blood.V110.11.1439.1439|issn=0006-4971}}</ref>.
|-
|Trisomy 8<ref name=":1" />
|Unknown
|Unknown
|Unknown
|Trisomy 8 and additional structural chromosomal changes are recurrent.<ref name=":1" />
|}
[[File:Dic(9 12).tif|center|thumb|577x577px|dic(9;12)(p13;p13), Image courtesy of Dr. Jennie Thurston, Parke Cytogenetics Laboratory]]
<br />
==Genomic Gain/Loss/LOH==
Trisomy 8 and additional structural chromosomal changes are recurrent.<ref name=":1" />
==Gene Mutations (SNV/INDEL)==
Put your text here and/or fill in the tables
{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
| || || || ||
|}
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
| ||
|-
| ||
|-
| ||
|}
==Epigenomics (Methylation)==
Put your text here
==Genes and Main Pathways Involved==
''PAX5'' gene encodes for a transcriptional factor essential for B-cell development. The role of ''PAX5/ETV6'' in leukemogenesis is not fully understood, although preliminary evidences suggested that the protein may have a repressor function on transcription.<ref name=":4">{{Cite journal|last=Fazio|first=Grazia|last2=Palmi|first2=Chiara|last3=Rolink|first3=Antonius|last4=Biondi|first4=Andrea|last5=Cazzaniga|first5=Giovanni|date=2008-01-01|title=PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells|url=https://pubmed.ncbi.nlm.nih.gov/18172310|journal=Cancer Research|volume=68|issue=1|pages=181–189|doi=10.1158/0008-5472.CAN-07-2778|issn=1538-7445|pmid=18172310}}</ref><ref name=":5">{{Cite journal|last=Fazio|first=G.|last2=Cazzaniga|first2=V.|last3=Palmi|first3=C.|last4=Galbiati|first4=M.|last5=Giordan|first5=M.|last6=te Kronnie|first6=G.|last7=Rolink|first7=A.|last8=Biondi|first8=A.|last9=Cazzaniga|first9=G.|date=2013-04|title=PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5|url=https://pubmed.ncbi.nlm.nih.gov/23090680|journal=Leukemia|volume=27|issue=4|pages=992–995|doi=10.1038/leu.2012.281|issn=1476-5551|pmid=23090680}}</ref>
{| class="wikitable"
|'''Gene;  Genetic Alteration'''
|'''Pathway'''
|'''Pathophysiologic  Outcome'''
|-
|''PAX5''
|
|The role of ''PAX5/ETV6'' in leukemogenesis is not fully understood, although preliminary evidences suggested that the protein may have a repressor function on transcription.<ref name=":4" /><ref name=":5" />
|}

==Diagnostic Testing Methods==

*Conventional cytogenetics
*Interphase FISH
*RT-PCR for ''PAX5/ETV6'' fusion
*Next Generation Sequencing (NGS)

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
This translocation is associated with an excellent prognosis.<ref>{{Cite journal|last=Mahmoud|first=H.|last2=Carroll|first2=A. J.|last3=Behm|first3=F.|last4=Raimondi|first4=S. C.|last5=Schuster|first5=J.|last6=Borowitz|first6=M.|last7=Land|first7=V.|last8=Pullen|first8=D. J.|last9=Vietti|first9=T. J.|date=1992-07|title=The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis|url=https://pubmed.ncbi.nlm.nih.gov/1625489|journal=Leukemia|volume=6|issue=7|pages=703–707|issn=0887-6924|pmid=1625489}}</ref> A single study showed at median follow-up of 5 years, 29/31 cases (94%) remain in first remission conferring an excellent prognosis to this leukemia.<ref name=":1" />

Children with dic(9;12) fare extremely well, regardless of the specific type of therapy or the presence of one or more established poor risk features.

==Familial Forms==
Put your text here
==Other Information==
Put your text here
==Links==
''[[PAX5]]''

''[[ETV6]]''
==References==
(use "Cite" icon at top of page)<references />

#

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
[[Category:HAEM4]] [[Category:DISEASE]]