View source for HAEM4Backup:Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1); RUNX1-RUNX1T1

==Primary Author(s)*==
Christine Bryke, MD<br>Beth Israel Deaconess Medical Center, Boston, MA

__TOC__

==Cancer Category/Type==

Acute myeloid leukemia

==Cancer Sub-Classification / Subtype==

Acute myeloid leukaemia (AML) with t(8;21)(q22;q22.1) resulting in RUNX1-RUNX1T1 fusion

==Definition / Description of Disease==

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 gene fusion defines a subtype of AML with neutrophil lineage maturation.  In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, it is in the group of AML with recurrent genetic abnormalities<ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref>. In the older French-American-British (FAB) classification system, t(8;21)(q22;q22) positive AML belonged to the acute myeloblastic leukemia with maturation M2 category and accounted for 10% of cases.  t(8;21)(q22;q22) can occasionally be seen in therapy-related AML.  In those instances the leukemia is not classified in the group of AML with recurrent genetic abnormalities due to clinical and prognostic differences.  AML with t(8;21)(q22;q22) is a core binding leukemia (see Genes and Main Pathways Involved section below)<ref>{{Cite journal|last=Sangle|first=Nikhil A.|last2=Perkins|first2=Sherrie L.|date=2011|title=Core-binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22032582|journal=Archives of Pathology & Laboratory Medicine|volume=135|issue=11|pages=1504–1509|doi=10.5858/arpa.2010-0482-RS|issn=1543-2165|pmid=22032582}}</ref>.

*t(8;21)(q22;q22) is a translocation involving the long arms of chromosomes 8 and 21 that defines a distinctive cytogenetic subtype of [[AML|acute myeloid leukemia]].
*Complex translocations involving chromosomes 8, 21 and a third chromosome occur; the derivative chromosome 8 in the t(8;21)(q22;q22) and the variant t(8;21;var) carries the RUNX1-RUNX1T1 gene rearrangement.
*Cases with cryptic RUNX1-RUNX1T1 gene rearrangement have been reported.
*Note: The RUNX1T1 gene is currently located at 8q21.3.  This gene was previously located at 8q22, which explains the discrepancy in the breakpoint given in the name for this WHO-defined disease entity.

<br>
[[File:T_8_21_q22_q22.png|frame|center| Karyogram showing t(8;21)(q22;q22) translocation.  Jennifer
Otani, Beth Israel Deaconess Medical Center, Boston, MA]]

[[File:t(8;21)(q22;q22).png|frame|center| t(8;21)(q22;q22)]]

[[File:RUNX1_RUNXT1_FISH_Inverted.png|frame|center| FISH RUNX1-RUNX1T1 probe set on metaphase cell with 
t(8;21)(q22;q22) translocation.  Jennifer Otani, Beth Israel
Deaconess Medical Center, Boston, MA.
]]

==Synonyms / Terminology==

AML1-ETO

==Epidemiology / Prevalence==

Approximately 1-5% of AML cases have the t(8;21)(q22;q22.1)

*Occurs mainly in younger patients
*Mean age is 30 years
*Most common type of AML in children

==Clinical Features==

*May present as a myeloid sarcoma and, if so, the bone marrow aspirate blast count may be misleadingly low
*Concurrent systemic mastocytosis has been reported.

==Sites of Involvement==

Bone marrow

==Morphologic Features==

*Large blasts with abundant basophilic cytoplasm often with azurophilic granules and perinuclear clearing
*Long sharp Auer rods are frequently observed.

<br>
[[File:AML_RUNX1_RUNXT1_Path.png|center|frame|Bone marrow aspirate with t(8;21)(q22;q22)
blast with Auer rod (100X).   Robert Willim, MD, 
Beth Israel Deaconess Medical Center, Boston, MA]]
<br>

*Promyelocytes, myelocytes and metamyelocytes may have abnormal nuclear segmentation and cytoplasmic staining.
*Normal eosinophil precursors are frequently increased and do not show the nuclear and cytoplasmic abnormalities seen in AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22).
*Cases with t(8;21)(q22;q22.1) and less than 20% blast percentage in the marrow should be classified as AML rather than myelodysplastic  syndrome according to the WHO 2017<ref>Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France.</ref>.

==Immunophenotype==

*Blasts express CD34, HLA-DR, MPO, CD13, CD33 (weak), CD15 and/or CD65, co-expression of CD34. Lymphoid markers: CD19, PAX5, sometimes cytoplasmic CD79a
*Occasional weak TdT positivity and/or CD56 expression may have adverse prognosis

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD34, HLA-DR, MPO, CD13, CD33 (weak), TdT (weak), CD56 (fraction of cases)
|-
|Positive (subset)||CD15 and/or CD65
|-
|Positive (Lymphoid markers)
|CD19, PAX5, sometimes cytoplasmic CD79a
|-
|Negative (universal)||
|-
|Negative (subset)||
|}<br />
==Chromosomal Rearrangements (Gene Fusions)==
{| class="wikitable sortable"
|-

|}
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(8;21)(q22;q22.1)||5' RUNX1 / 3'RUNX1T1||der(8)||1- 5% of AML
|}

==Characteristic Chromosomal Aberrations / Patterns==

Additional aberrations in >70% of cases with t(8;21); common loss of a sex chromosome or deletion 9q

==Genomic Gain/Loss/LOH==

9q22 loss

==Gene Mutations (SNV/INDEL)==

AML with t(8;21)(q22;q22) has genetic heterogeneity at the molecular level.  Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis.

*''KIT'' mutations occur in 20-25% of cases and are associated with a high risk of relapse in AML with t(8;21)(q22;q22)<ref>{{Cite journal|last=Paschka|first=Peter|last2=Marcucci|first2=Guido|last3=Ruppert|first3=Amy S.|last4=Mrózek|first4=Krzysztof|last5=Chen|first5=Hankui|last6=Kittles|first6=Rick A.|last7=Vukosavljevic|first7=Tamara|last8=Perrotti|first8=Danilo|last9=Vardiman|first9=James W.|date=2006|title=Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study|url=https://www.ncbi.nlm.nih.gov/pubmed/16921041|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=24|issue=24|pages=3904–3911|doi=10.1200/JCO.2006.06.9500|issn=1527-7755|pmid=16921041}}</ref>. Patients with ''KIT'' mutations have a significantly shorter overall survival and disease free survival periods than those without KIT mutations<ref>{{Cite journal|last=Kim|first=Hee-Jin|last2=Ahn|first2=Hee Kyung|last3=Jung|first3=Chul Won|last4=Moon|first4=Joon Ho|last5=Park|first5=Chang-Hun|last6=Lee|first6=Ki-O.|last7=Kim|first7=Sun-Hee|last8=Kim|first8=Yeo-Kyeoung|last9=Kim|first9=Hyeoung-Joon|date=2013|title=KIT D816 mutation associates with adverse outcomes in core binding factor acute myeloid leukemia, especially in the subgroup with RUNX1/RUNX1T1 rearrangement|url=https://www.ncbi.nlm.nih.gov/pubmed/23053179|journal=Annals of Hematology|volume=92|issue=2|pages=163–171|doi=10.1007/s00277-012-1580-5|issn=1432-0584|pmid=23053179}}</ref>.

*In a study of 139 t(8;21)(q22;q22) AML patients were investigated for possible mutations in ''KIT'' and 10 other genes (''ASXL1'', ''FLT3'', ''NPM1'', ''MLL'', ''IDH1'', ''IDH2'', ''KRAS'', ''NRAS'', ''CBL'', and ''JAK2'')<ref name=":0">{{Cite journal|last=Krauth|first=M.-T.|last2=Eder|first2=C.|last3=Alpermann|first3=T.|last4=Bacher|first4=U.|last5=Nadarajah|first5=N.|last6=Kern|first6=W.|last7=Haferlach|first7=C.|last8=Haferlach|first8=T.|last9=Schnittger|first9=S.|date=2014|title=High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome|url=https://www.ncbi.nlm.nih.gov/pubmed/24402164|journal=Leukemia|volume=28|issue=7|pages=1449–1458|doi=10.1038/leu.2014.4|issn=1476-5551|pmid=24402164}}</ref>.  49.6% had one mutation in addition to the t(8;21)(q22;q22).  These were most often ''KIT'', ''NRAS'' and ''ASXL1''.  16.5% of patients had ≥2 mutations.  Infrequent accompanying mutated genes found in only 2.9-5% of cases include in decreasing frequency:  ''FLT3''-ITD, ''FLT3''-TKD, ''CBL'', and ''KRAS'', ''IDH2'' and ''JAK2''.  These mutations did not adversely affect prognosis.  ''NPM1'' mutations are thought to be mutually exclusive of RUNX1-RUNX1T1.

*''ASXL2'' mutations have been identified in greater than 20% of patients with t(8;21), but not in patients with inv(16)/t(16;16) or RUNX1-mutated AML<ref name=":1">{{Cite journal|last=Micol|first=Jean-Baptiste|last2=Duployez|first2=Nicolas|last3=Boissel|first3=Nicolas|last4=Petit|first4=Arnaud|last5=Geffroy|first5=Sandrine|last6=Nibourel|first6=Olivier|last7=Lacombe|first7=Catherine|last8=Lapillonne|first8=Helene|last9=Etancelin|first9=Pascaline|date=2014|title=Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations|url=https://www.ncbi.nlm.nih.gov/pubmed/24973361|journal=Blood|volume=124|issue=9|pages=1445–1449|doi=10.1182/blood-2014-04-571018|issn=1528-0020|pmc=4148766|pmid=24973361}}</ref>. ''ASXL2'' mutations are similarly frequent in adults and children with t(8;21) and are mutually exclusive with ''ASXL1'' mutations.  Although overall survival is similar between ''ASXL1'' and ''ASXL2'' mutant t(8;21) AML patients and their wild-type counterparts, patients with ''ASXL1'' or ''ASXL2'' mutations had a cumulative incidence of relapse that is significantly higher than with their ''ASXL1'' or ''ASXL2'' wild-type counterparts<ref name=":1" />.

*Recurring ''ZBTB7A'' mutations have been identified in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ''ZBTB7A''<ref name=":2">{{Cite journal|last=Hartmann|first=Luise|last2=Dutta|first2=Sayantanee|last3=Opatz|first3=Sabrina|last4=Vosberg|first4=Sebastian|last5=Reiter|first5=Katrin|last6=Leubolt|first6=Georg|last7=Metzeler|first7=Klaus H.|last8=Herold|first8=Tobias|last9=Bamopoulos|first9=Stefanos A.|date=2016|title=ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation|url=https://www.ncbi.nlm.nih.gov/pubmed/27252013|journal=Nature Communications|volume=7|pages=11733|doi=10.1038/ncomms11733|issn=2041-1723|pmc=4895769|pmid=27252013}}</ref>. The transcription factor ''ZBTB7A'' is important for hematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, it has been shown that ''ZBTB7A'' mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ''ZBTB7A''. The specific association of ''ZBTB7A'' mutations with t(8;21) rearranged AML points towards leukemogenic cooperativity between mutant ''ZBTB7A'' and the RUNX1/RUNX1T1 fusion<ref name=":2" />.

*''WT1'' mutations have been found to be relatively common (13.8%) in core binding factor leukemia<ref>{{Cite journal|last=Park|first=Sang Hyuk|last2=Lee|first2=Hyun Ji|last3=Kim|first3=In-Suk|last4=Kang|first4=Jeong-Eun|last5=Lee|first5=Eun Yup|last6=Kim|first6=Hyeoung-Joon|last7=Kim|first7=Yeo-Kyeoung|last8=Won|first8=Jong-Ho|last9=Bang|first9=Soo Mee|date=2015|title=Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean Population|url=https://www.ncbi.nlm.nih.gov/pubmed/25932436|journal=Annals of Laboratory Medicine|volume=35|issue=3|pages=288–297|doi=10.3343/alm.2015.35.3.288|issn=2234-3814|pmc=4390696|pmid=25932436}}</ref>. Low ''WT1'' transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation<ref>{{Cite journal|last=Qin|first=Ya-Zhen|last2=Wang|first2=Yu|last3=Zhu|first3=Hong-Hu|last4=Gale|first4=Robert Peter|last5=Zhang|first5=Mei-Jie|last6=Jiang|first6=Qian|last7=Jiang|first7=Hao|last8=Xu|first8=Lan-Ping|last9=Chen|first9=Huan|date=2016|title=Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation|url=https://www.ncbi.nlm.nih.gov/pubmed/27197573|journal=Chinese Journal of Cancer|volume=35|pages=46|doi=10.1186/s40880-016-0110-6|issn=1944-446X|pmc=4873994|pmid=27197573}}</ref>.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|KIT|| || || ||20-30%
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||NRAS and ASXL1
|-
|Secondary Mutations||
|-
|Mutually Exclusive||ASXL1 and ASXL2
|}

==Epigenomics (Methylation)==

None

==Genes and Main Pathways Involved==

Genes:

*''RUNX1T1'' (also known as ''ETO'') on 8q22 is transcribed from telomere to centromere; 3 proline rich domains; 2 zinc finger, and a PEST region in the C-terminus; tissue restricted expression; nuclear localization; putative transcription factor.

*''RUNX1'' (also known as ''AML1'' and ''CBFA'') on 21q22; contains a runt domain and a transactivation domain in the C-terminus; forms heterodimers; widely expressed; nuclear localization; transcription factor (activator) for various hematopoietic-specific genes.


DNA:

*t(8;21)(q22;q22) results in a 5’RUNX1-3’RUNX1T1 hybrid gene involving fusion of the very 5’ end of the ''RUNX1T1'' gene to ''RUNX1'' in an ~25 kb breakpoint region between exons 5 and 6.


Protein:

*A fusion protein with the N-terminus runt domain (responsible for DNA binding and protein-protein interaction) of ''RUNX1'' fused to the 577 C-terminal residues of ''RUNX1T1''.  The reciprocal product is not detected. The fusion protein retains the ability to recognize the ''RUNX1'' consensus DNA binding site (it is a negative dominant competitor with the normal ''RUNX1'') and to dimerize with the CBFβ subunit in the heterodimeric core binding factor.  The core binding factor is a transcription factor that plays an essential role in regulation of normal hematopoiesis.  It is composed of a DNA-binding CBFα (''RUNX1'') chain and a non-DNA-binding CBFβ chain.  It is likely oncogenic due to altered transcriptional regulation of normal ''RUNX1'' target genes.  Animal studies suggest that the fusion proteins alone are not able to induce leukemia and that additional genetic alterations are required for leukemogenic transformation<ref>{{Cite journal|last=Speck|first=Nancy A.|last2=Gilliland|first2=D. Gary|date=2002|title=Core-binding factors in haematopoiesis and leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/12094236|journal=Nature Reviews. Cancer|volume=2|issue=7|pages=502–513|doi=10.1038/nrc840|issn=1474-175X|pmid=12094236}}</ref><ref>{{Cite journal|last=Downing|first=James R.|date=2003|title=The core-binding factor leukemias: lessons learned from murine models|url=https://www.ncbi.nlm.nih.gov/pubmed/12573435|journal=Current Opinion in Genetics & Development|volume=13|issue=1|pages=48–54|doi=10.1016/s0959-437x(02)00018-7|issn=0959-437X|pmid=12573435}}</ref>.
	

Key cellular pathways:

*The normal transcriptional activity of the RUNX1 protein in the core binding factor is affected in a negative manner by the chimeric protein encoded by the RUNX1-RUNX1T1 fusion gene.  It has been proposed that the RUNX1-RUNX1T1 protein recruits histone deacetylases and DNA methyl transferase 1 to core binding factor target genes<ref>{{Cite journal|last=Marcucci|first=Guido|date=2006|title=Core binding factor acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/16728942|journal=Clinical Advances in Hematology & Oncology: H&O|volume=4|issue=5|pages=339–341|issn=1543-0790|pmid=16728942}}</ref>. This leads to increased chromatin deacetylation and promotor hypermethylation, resulting in gene transcriptional repression and disruption of normal cellular pathways of hematopoiesis.

==Diagnostic Testing Methods==

*Chromosome analysis, FISH, RT-PCR
*FISH or RT-PCR is needed for cytogenetically cryptic cases with typical blast morphology and immunophenotype
*RT-PCR is employed for minimal residual disease detection

<br>
[[File:RUNX1_RUNXT1_FISH.png|center|frame|FISH with RUNX1-RUNX1T1 probe set on interphase cells with t(8;21)(q22;q22) translocation.  Nancy Hsu and Min Zhang, Beth Israel Deaconess Medical Center, Boston, MA.]]
<br>

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
Diagnostic:

*The presence of t(8;21)(q22;q22) is diagnostic of a cytogenetic subtype of acute myeloid leukemia with maturation in the neutrophilic lineage.
*When t(8;21)(q22;q22) is present the diagnosis of acute myeloid leukemia is made regardless of a blast count less than 20%.


Prognostic:

*t(8;21)(q22;q22) positive AML usually has a good response to chemotherapy and a high complete remission rate with long-term disease-free survival when treated with high dose cytarabine in the consolidation phase.  Factors that appear to adversely affected prognosis include CD56 expression and ''KIT'' gene mutations.  The prognostic significance of other accompanying gene mutations is under investigation.


Therapeutic target:

*t(8;21)(q22;q22) positive AML currently has no molecular target for drug therapy.
*Standard induction 7 + 3 chemotherapy regimen of cytarabine for 7 days plus an anthracycline or anthracenedione for 3 days.  In first complete remission patients younger than 60 years without a KIT mutation are treated with high dose cytarabine consolidation therapy.  If a ''KIT'' mutation is present, bone marrow transplant is performed in first complete remission<ref>{{Cite journal|last=Tallman|first=Martin S.|last2=Wang|first2=Eunice S.|last3=Altman|first3=Jessica K.|last4=Appelbaum|first4=Frederick R.|last5=Bhatt|first5=Vijaya Raj|last6=Bixby|first6=Dale|last7=Coutre|first7=Steven E.|last8=De Lima|first8=Marcos|last9=Fathi|first9=Amir T.|date=2019-06-01|title=Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology|url=https://pubmed.ncbi.nlm.nih.gov/31200351|journal=Journal of the National Comprehensive Cancer Network: JNCCN|volume=17|issue=6|pages=721–749|doi=10.6004/jnccn.2019.0028|issn=1540-1413|pmid=31200351}}</ref>.
*Recently homoharringtonine, aclarubicin and cytarabine as the first course of induction therapy has been found to be highly effective for acute myeloid leukemia with t(8;21)(q22;q22)<ref name=":0" />.

==Familial Forms==

None

==Other Information==

None

==Links==

[[RUNX1]]

[[RUNX1T1]]

[https://cancer.sanger.ac.uk/cosmic/gene/analysis?all_data=&coords=AA%3AAA&dr=&end=977&gd=&hn=haematopoietic_neoplasm&id=11&ln=KIT&meth=H&meth=L&seqlen=977&sh=acute_myeloid_leukaemia&sn=haematopoietic_and_lymphoid_tissue&ss=NS&start=1#ts KIT mutations in AML COSMIC database]

[http://www.uptodate.com/contents/cytogenetics-in-acute-myeloid-leukemia| www.uptodate.com cytogenetics in AML]
<br>
[http://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:10471| www.genenames.org RUNX1]
<br>
[http://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:1535| www.genenames.org RUNX1T1]

==References==
<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.

Edited by: Fabiola Quintero-Rivera 7/21/2018


[[Category:Translocation]]
[[Category:Translocation Chromosome 8]]
[[Category:Translocation Chromosome 21]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 8]]
[[Category:Structural Abnormalities Chromosome 21]]
[[Category:Fusion Genes in AML]]
[[Category:Fusion Genes R]]
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