Compendium of Cancer Genome Aberrations

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{{DISPLAYTITLE:Myeloid proliferations associated with Down syndrome}}
{{DISPLAYTITLE:Myeloid proliferations associated with Down syndrome}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


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{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome]].
<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome]].
Other relevent pages include: [[HAEM4:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome]], [[HAEM4:Myeloid Leukemia Associated with Down Syndrome]]
Other relevent pages include: [[HAEM4:Transient Abnormal Myelopoiesis (TAM) Associated with Down Syndrome]], [[HAEM4:Myeloid Leukemia Associated with Down Syndrome]]


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==Definition / Description of Disease==
This is a distinct entity in the World Health Organization (WHO) classification system within the section of [[HAEM4:Myeloid Proliferations Associated with Down Syndrome]]<ref name=":0">Arber DA, et al., (2017). Myeloid proliferations associated with Down syndrome, 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, p169-170.</ref>.
Transient abnormal myelopoiesis (TAM) associated with Down syndrome (DS) is a unique disorder of newborns with DS that presents with clinical and morphological findings indistinguishable from those of acute myeloid leukemia. The blasts have morphological and immunological features of megakaryocytic lineage<ref name=":0" /><ref name=":1">{{Cite journal|last=Klusmann|first=Jan-Henning|last2=Creutzig|first2=Ursula|last3=Zimmermann|first3=Martin|last4=Dworzak|first4=Michael|last5=Jorch|first5=Norbert|last6=Langebrake|first6=Claudia|last7=Pekrun|first7=Arnulf|last8=Macakova-Reinhardt|first8=Katarina|last9=Reinhardt|first9=Dirk|date=2008|title=Treatment and prognostic impact of transient leukemia in neonates with Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/18182574|journal=Blood|volume=111|issue=6|pages=2991–2998|doi=10.1182/blood-2007-10-118810|issn=0006-4971|pmc=2265448|pmid=18182574}}</ref><ref name=":2">{{Cite journal|last=Gruber|first=Tanja A.|last2=Downing|first2=James R.|date=2015|title=The biology of pediatric acute megakaryoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/26186939|journal=Blood|volume=126|issue=8|pages=943–949|doi=10.1182/blood-2015-05-567859|issn=1528-0020|pmc=4551356|pmid=26186939}}</ref><ref name=":3">{{Cite journal|last=Bhatnagar|first=Neha|last2=Nizery|first2=Laure|last3=Tunstall|first3=Oliver|last4=Vyas|first4=Paresh|last5=Roberts|first5=Irene|date=2016|title=Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update|url=https://www.ncbi.nlm.nih.gov/pubmed/27510823|journal=Current Hematologic Malignancy Reports|volume=11|issue=5|pages=333–341|doi=10.1007/s11899-016-0338-x|issn=1558-822X|pmc=5031718|pmid=27510823}}</ref><ref name=":4">{{Cite journal|last=Bombery|first=Melissa|last2=Vergilio|first2=Jo-Anne|date=2014|title=Transient abnormal myelopoiesis in neonates: GATA get the diagnosis|url=https://www.ncbi.nlm.nih.gov/pubmed/25268193|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=10|pages=1302–1306|doi=10.5858/arpa.2014-0304-CC|issn=1543-2165|pmid=25268193}}</ref><ref name=":5">{{Cite journal|last=Saida|first=Satoshi|date=2016|title=Evolution of myeloid leukemia in children with Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26910243|journal=International Journal of Hematology|volume=103|issue=4|pages=365–372|doi=10.1007/s12185-016-1959-5|issn=1865-3774|pmid=26910243}}</ref>.
==Synonyms / Terminology==
Tansient myeloproliferative disorder (TMD)
==Epidemiology / Prevalence==
TAM is diagnosed in ~10% of newborns with DS, but the true incidence is higher because not all newborns are symptomatic.  TAM uncommonly occurs in phenotypically normal neonates with trisomy 21 mosaicism, and is extremely rare in neonates without chromosome 21 abnormalities<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" />.
==Clinical Features==
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Transient abnormal myelopoiesis occurs exclusively in patients with Down syndrome (constitutional trisomy 21), and affects approximately 4% to 10% of neonates. TAM manifests in the neonatal period, and is characterized by circulating megakaryoblasts with varied degrees of multisystem organ involvement. The median age of presentation is 3 to 7 days, though patients may be diagnosed at up to 2 months of life. The most common clinical manifestations include hepatomegaly (60%), splenomegaly (35%–40%), jaundice (15%), pericardial effusion (15%), pleural effusion (10%–15%), ascites (10%), respiratory distress (10%), and bleeding diathesis (10%). Less common features include hepatic fibrosis, hydrops fetalis, and renal failure. Characteristic hematologic findings include leukocytosis (WBC > 100K/μL in 20%–30%), thrombocytopenia (40%), and increased numbers of circulating blasts. Approximately 10% to 25% of patients are asymptomatic; thus, the diagnosis may be established as an incidental finding during laboratory assessment for some other cause. Occasionally, the finding of TAM may even be the first indication that a patient has trisomy 21.
The natural history of TAM is quite variable. Most neonates (80% with documented TAM) undergo spontaneous remission within 3 to 6 months of age. At the other end of the disease spectrum, neonatal (or even fetal) demise occurs in approximately 10% of patients secondary to diffuse organ infiltration by megakaryoblasts, associated parenchymal fibrosis, and subsequent multisystem failure. Independent risk factors that portend early mortality include WBC counts above 100 K/μL, preterm delivery (<37 weeks), effusions (pleural, pericardial, ascites, or hydrops), coagulopathy, bleeding diathesis, platelet count greater than 100K/μL, low birth weight, and failure to clear peripheral blasts. When these high-risk features are present, chemotherapeutic intervention is warranted.
Approximately 20% of patients with TAM develop AMKL within the first 4 years of life and this may be preceded by a myelodysplastic-like syndrome. The World Health Organization classification category “myeloid leukemia associated with DS” (DS-AMKL) encompasses both myelodysplastic and leukemic manifestations regardless of blast percentage. The median age of onset is 2 years, younger than that seen in non–DS-AMKL. Patients typically manifest with low WBC count, cytopenia, organomegaly, progressive marrow fibrosis, and clonal cytogenetic abnormalities, e.g., trisomy 8. Blasts in DS-AMKL are morphologically and immunophenotypically similar to those seen in TAM. Patients with DS-AMKL have a favorable prognosis with 80% 3-year overall survival. This response rate is, in part, attributed to enhanced chemosensitivity of megakaryoblasts to cytarabine. The cytidine deaminase gene functions in cytarabine catabolism, and its transcription is diminished in DS, which may lead to diminished intracellular drug metabolism and consequent increased drug efficacy<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" />.
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==Sites of Involvement==
Blood and bone marrow are the principle sites of involvement. Extramedullary involvement, mainly of the spleen and liver, is almost always present as well<ref name=":0" />.
==Morphologic Features==
The morphological and immunophenotypic features of TAM are similar to those seen in most cases of acute myeloid leukemia associated with DS<ref name=":0" />. Peripheral blood and bone marrow blasts often have basophilic cytoplasm and coarse basophilic granules and cytoplasmic blebbing suggestive of megakaryoblasts. Some patients have peripheral blood basophilia; erythroid and megakaryocytic dysplasia is often present in the bone marrow. No critical threshold has been established for blast percentage in the diagnosis of TAM. Circulating blasts can often be seen in both neonates without DS, especially those who are ill or premature, and neonates with DS, emphasizing the importance of manual peripheral smear review as well as ancillary laboratory studies in the evaluation [5]. Bone marrow examination may not be indicated as marrow findings are either similar to, or less pronounced than, those in blood<ref name=":4" />.
[[File:ML-DS.jpeg|frame|center|PB-myeloblast with open nuclear chromatin and basophilic cytoplasm on left; BM-myeloblasts with round to irregular nuclei, fine reticular nuclear chromatin, prominent nucleoli, basophilic cytoplasm with vacuoles. Some blasts show nuclear blebs. No Auer rods]]
==Immunophenotype==
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|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
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|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
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Phenotypically, blasts commonly express stem cell (variable CD34, CD117), myeloid (CD13, CD33), nonlineage (CD4, CD7, CD56), and megakaryoblastic/megakaryocytic (CD61, CD41, CD42) antigens<ref name=":4" />.
The blasts in TAM have a characteristic megakaryoblastic immunophenotype. In most cases, the leukemic blasts are positive for CD34, KIT (CD117), CD13, CD33, HLA-DR, CD4 (dim), CD41, CD42, CD110 (TPOR), IL3R, CD36, CD61, and CD71, often with expression of CD7 and CD56. The blasts are negative for MPO, CD15, CD14, CD11a, and glycophorin A. IHC with CD41, CD42b, and CD 61 may be particularly useful for identifying blasts of megakaryocytic lineage in BM biopsies<ref name=":0" />.
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==WHO Essential and Desirable Genetic Diagnostic Criteria==
==WHO Essential and Desirable Genetic Diagnostic Criteria==
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* Chromosomal Rearrangements (Gene Fusions)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
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The disease evolution of TAM and DS-AMKL is currently conceived as a sequential multistep process of leukemogenesis. Trisomy 21 represents the critical “initiating” event. ''GATA1'' mutation reflects a “secondary hit” to fetal liver hematopoiesis, particularly megakaryocytic-erythroid progenitors, that leads to TAM and confers some selective advantage.  
The disease evolution of TAM and DS-AMKL is currently conceived as a sequential multistep process of leukemogenesis. Trisomy 21 represents the critical “initiating” event. ''GATA1'' mutation reflects a “secondary hit” to fetal liver hematopoiesis, particularly megakaryocytic-erythroid progenitors, that leads to TAM and confers some selective advantage.  


Given the risk of progression to DS-AMKL, some advocate that all neonates with DS undergo routine screening for TAM with manual peripheral blood smear review and ''GATA1'' mutation analysis. With detection of a ''GATA1'' mutation, clinical assessment and routine laboratory screening is then suggested periodically throughout early childhood<ref name=":0" /><ref name=":4" />.
Given the risk of progression to DS-AMKL, some advocate that all neonates with DS undergo routine screening for TAM with manual peripheral blood smear review and ''GATA1'' mutation analysis. With detection of a ''GATA1'' mutation, clinical assessment and routine laboratory screening is then suggested periodically throughout early childhood<ref name=":0">Arber DA, et al., (2017). Myeloid proliferations associated with Down syndrome, 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, p169-170.</ref><ref name=":4">{{Cite journal|last=Bombery|first=Melissa|last2=Vergilio|first2=Jo-Anne|date=2014|title=Transient abnormal myelopoiesis in neonates: GATA get the diagnosis|url=https://www.ncbi.nlm.nih.gov/pubmed/25268193|journal=Archives of Pathology & Laboratory Medicine|volume=138|issue=10|pages=1302–1306|doi=10.5858/arpa.2014-0304-CC|issn=1543-2165|pmid=25268193}}</ref>.


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Constitutional trisomy 21 or mosaic constitutional trisomy 21
Constitutional trisomy 21 or mosaic constitutional trisomy 21
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


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In addition to trisomy 21, acquired ''GATA1'' mutations are present in blast cells of TAM [1].
In addition to trisomy 21, acquired ''GATA1'' mutations are present in blast cells of TAM [1].
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In normal human development, the liver is the primary site of fetal (in utero) hematopoiesis. With birth, the hepatic microenvironment changes such that liver hematopoiesis is down-regulated while bone marrow simultaneously assumes this primary functionality. Given the clinical and laboratory manifestations of TAM, which include leukocytosis and circulating megakaryoblasts, often with hepatomegaly, TAM reflects perturbation of this normal developmental process. Transient abnormal myelopoiesis may arise in utero within the fetal liver with “spontaneous resolution” reflecting the natural process of hepatic hematopoietic down-regulation. 
In normal human development, the liver is the primary site of fetal (in utero) hematopoiesis. With birth, the hepatic microenvironment changes such that liver hematopoiesis is down-regulated while bone marrow simultaneously assumes this primary functionality. Given the clinical and laboratory manifestations of TAM, which include leukocytosis and circulating megakaryoblasts, often with hepatomegaly, TAM reflects perturbation of this normal developmental process. Transient abnormal myelopoiesis may arise in utero within the fetal liver with “spontaneous resolution” reflecting the natural process of hepatic hematopoietic down-regulation. 


TAM is the result of a multistep process in which trisomy 21 is the “initiating” event in disease pathogenesis. Trisomy 21 creates an environment, in utero, in which hematopoietic progenitor cells within fetal liver are primed for acquisition of either single or multiple somatic ''GATA1'' mutations that reflect a “secondary hit,” thereby promoting hematopoietic dysregulation and emergence of TAM. With birth, hematopoiesis naturally transitions from fetal liver to bone marrow and the ''GATA1'' megakaryoblastic clone becomes quiescent. However, this clone persists over time and undergoes other somatic mutations and epigenetic events ultimately lead to the impaired megakaryocytic differentiation and uncontrolled proliferation characteristic of DS-AMKL<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" />.
TAM is the result of a multistep process in which trisomy 21 is the “initiating” event in disease pathogenesis. Trisomy 21 creates an environment, in utero, in which hematopoietic progenitor cells within fetal liver are primed for acquisition of either single or multiple somatic ''GATA1'' mutations that reflect a “secondary hit,” thereby promoting hematopoietic dysregulation and emergence of TAM. With birth, hematopoiesis naturally transitions from fetal liver to bone marrow and the ''GATA1'' megakaryoblastic clone becomes quiescent. However, this clone persists over time and undergoes other somatic mutations and epigenetic events ultimately lead to the impaired megakaryocytic differentiation and uncontrolled proliferation characteristic of DS-AMKL<ref name=":1">{{Cite journal|last=Klusmann|first=Jan-Henning|last2=Creutzig|first2=Ursula|last3=Zimmermann|first3=Martin|last4=Dworzak|first4=Michael|last5=Jorch|first5=Norbert|last6=Langebrake|first6=Claudia|last7=Pekrun|first7=Arnulf|last8=Macakova-Reinhardt|first8=Katarina|last9=Reinhardt|first9=Dirk|date=2008|title=Treatment and prognostic impact of transient leukemia in neonates with Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/18182574|journal=Blood|volume=111|issue=6|pages=2991–2998|doi=10.1182/blood-2007-10-118810|issn=0006-4971|pmc=2265448|pmid=18182574}}</ref><ref name=":2">{{Cite journal|last=Gruber|first=Tanja A.|last2=Downing|first2=James R.|date=2015|title=The biology of pediatric acute megakaryoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/26186939|journal=Blood|volume=126|issue=8|pages=943–949|doi=10.1182/blood-2015-05-567859|issn=1528-0020|pmc=4551356|pmid=26186939}}</ref><ref name=":3">{{Cite journal|last=Bhatnagar|first=Neha|last2=Nizery|first2=Laure|last3=Tunstall|first3=Oliver|last4=Vyas|first4=Paresh|last5=Roberts|first5=Irene|date=2016|title=Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update|url=https://www.ncbi.nlm.nih.gov/pubmed/27510823|journal=Current Hematologic Malignancy Reports|volume=11|issue=5|pages=333–341|doi=10.1007/s11899-016-0338-x|issn=1558-822X|pmc=5031718|pmid=27510823}}</ref><ref name=":4" />.


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==Notes==
==Notes==
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<nowiki>*</nowiki>''Citation of this Page'': “Myeloid proliferations associated with Down syndrome”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myeloid_proliferations_associated_with_Down_syndrome</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Myeloid proliferations associated with Down syndrome”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myeloid_proliferations_associated_with_Down_syndrome</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases M]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases M]]
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