View source for HAEM4:Myeloid Proliferations Associated with Down Syndrome

==Primary Author(s)*==

Patricia T. Greipp. D.O.

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==General Disease Overview / Description of Cancer Category==

Children with Down syndrome (DS), or constitutional trisomy 21 (OMIM #190685), harbor an increased risk (up to 150-fold over and above that for individuals without DS) for the development of acute myeloid leukemia (DS-ML) and an increased risk extends into adulthood. Newborns with Down syndrome have a predisposition for the development of a unique myeloproliferative disorder called transient abnormal myelopoiesis (TAM) which can be difficult to differentiate from AML and resolves spontaneously, usually in less than three months. However, a subset of these individuals go on to develop AML (20-30%) within one to three years. Both of these entities (DS-ML and TAM) are recognized in the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues as “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>.

==WHO Classification Pages (Includes Links to Content)==

*[[HAEM5:Myeloid proliferations associated with Down syndrome]]
*[[HAEM5:Myeloid proliferations associated with Down syndrome]]

==Other Related Pages (Includes Links to Content)==

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==Additional Information==

Transient abnormal myelopoiesis (TAM) associated with Down syndrome occurs in 10% of neonates, usually within the first 3-7 days of life<ref>{{Cite journal|last=Zipursky|first=A.|last2=Brown|first2=E.|last3=Christensen|first3=H.|last4=Sutherland|first4=R.|last5=Doyle|first5=J.|date=1997|title=Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9190039|journal=Seminars in Perinatology|volume=21|issue=1|pages=97–101|doi=10.1016/s0146-0005(97)80025-0|issn=0146-0005|pmid=9190039}}</ref><ref>{{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>, but since some patients are asymptomatic, the incidence is believed to be higher. Characteristically, leukocytosis with thrombocytopenia is present as well as circulating blasts, while bone marrow demonstrates megakaryocytic proliferation and basophilia<ref name=":0" />. Clinical features can include hepatosplenomegaly, plural or cardiac effusions, skin rash and organ failure. Acquired mutations in the ''GATA1'' gene on the X chromosome (97% in exon 3 and the remainder in exon 3.1) were described in 2002 and are known to occur prenatally while hematopoiesis is active in the fetal liver<ref>{{Cite journal|last=Wechsler|first=Joshua|last2=Greene|first2=Marianne|last3=McDevitt|first3=Michael A.|last4=Anastasi|first4=John|last5=Karp|first5=Judith E.|last6=Le Beau|first6=Michelle M.|last7=Crispino|first7=John D.|date=2002|title=Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12172547|journal=Nature Genetics|volume=32|issue=1|pages=148–152|doi=10.1038/ng955|issn=1061-4036|pmid=12172547}}</ref>. The resultant truncated protein promotes megakaryocytic proliferation. ''GATA1'' mutations are present in the blast cells of all cases of TAM and DS-ML and are recognized as pathognomonic. Upon spontaneous resolution of TAM, the ''GATA1'' mutated cells undergo clonal extinction. However, full clonal extinction may not occur and the acquisition of secondary mutations (particularly in ''EZH2'', ''CTCF'', ''KANKSL1'', ''SH2B3'' and ''RAS'' pathway genes and sometimes ''JAK1'', ''JAK2'', ''JAK3'') lead to manifestation of DS-ML<ref>{{Cite journal|last=Cantor|first=Alan B.|date=2015|title=Myeloid Proliferations Associated with Down Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26753010|journal=Journal of Hematopathology|volume=8|issue=3|pages=169–176|doi=10.1007/s12308-014-0225-0|issn=1868-9256|pmc=4704699|pmid=26753010}}</ref>. DS-ML usually presents with a low leukocyte count, and pancytopenia is common with megakaryocytic blasts. However, the classic translocation associated with sporadic acute megakaryocytic leukemia (AMKL), t(1;22) with fusion of RBM15-MKL1, is not present. Monosomy 7 is also rare. Commonly acquired cytogenetic abnormalities in DS-ML include trisomy 8, 1q duplication, and 16q deletion<ref name=":1">{{Cite journal|last=Blink|first=Marjolein|last2=van den Heuvel-Eibrink|first2=Marry M.|last3=Aalbers|first3=Anna M.|last4=Balgobind|first4=Brian V.|last5=Hollink|first5=Iris H. I. M.|last6=Meijerink|first6=Jules P. P.|last7=van der Velden|first7=Vincent H. J.|last8=Beverloo|first8=Berna H.|last9=de Haas|first9=Valerie|date=2012|title=High frequency of copy number alterations in myeloid leukaemia of Down syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/22775985|journal=British Journal of Haematology|volume=158|issue=6|pages=800–803|doi=10.1111/j.1365-2141.2012.09224.x|issn=1365-2141|pmid=22775985}}</ref>. Also in counterdistinction to AML in children without Down syndrome (particularly children <5 years of age), the clinical outcome for children with DS-ML with ''GATA1'' mutation is favorable. These children should be treated with and adjusted chemotherapeutic regimen for AML. The outlook for children with DS-ML who relapse is poor<ref name=":1" />.


[[File:Natural_history_and_pathogenesis_of_TAM_and_ML-DS_(Bhatnagar,_et_al._2016).jpg]]
Natural History and Pathogenesis of TAM and ML-DS<ref>{{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>

==References==
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==Notes==
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<nowiki>*</nowiki>The hierarchical tumour classification structure displayed on this page is reproduced from the [https://tumourclassification.iarc.who.int/welcome/ WHO Classification of Tumours] with permission from the copyright holder, ©International Agency for Research on Cancer.


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