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trisomy 21-associated acute myeloid leukemia

Tuesday 9 November 2010

Children with Down syndrome (DS) have an approximately 50-fold increased risk of developing AML in the first 5 years of life, as compared to those without DS.

About 1-2% of children with DS develop AML, with the great majority being megakaryoblastic. In contrast, this morphological variant of AML is very rare (about 5% of AML) in children of corresponding age without DS.

DS-associated AML develops predominantly in the first 3 years of life. In most cases it occurs de novo but is occasionally preceded by a history of transient abnormal myelopoiesis (TAM).

In some cases, a pre-leukemic phase which is morphologically comparable to refractory cytopenia of childhood may last for several months before AML develops.

In patients with frank AML, blast cells often have basophilic cytoplasm with coarse basophilic granules and cytoplasmic blebs suggesting megakaryoblasts.

Bone marrow trephine is an important diagnostic tool since it usually reveals a dense network of reticulum fibres (responsible for frequent “punctio sicca“) and a marked increase in megakaryocytes with clusters of dysplastic small forms, micromegakaryocytes, and less frequently megakaryoblasts.

Blasts are CD117+, CD13+, CD33+, CD7+, CD41+, CD61+, CD14-, myeloperoxidase-, and glycophorin-negative. CD34 is expressed in about 50% of cases.

At immunohistochemistry on bone marrow paraffin sections, monoclonal antibodies directed against fixative-resistant epitopes of the CD41 and CD61 and LAT molecules are particularly helpful in detecting cells of megakaryocytic lineage.

As in transient abnormal myelopoiesis (TAM), blast cells carry mutations of the gene encoding the GATA1 transcription factor.

AML in children with DS who are over 5 years old and do not bear GATA1 mutations should be regarded as “conventional” AML.

The clinical outcome of GATA1-mutated acute myeloid leukemia (LAM) in young children with DS is characterized by excellent response to chemotherapy and very favorable prognosis compared with AML in children without DS.

However, there is an ongoing debate on what should be the best chemotherapeutic schedules for these patients.


- New classification of acute myeloid leukemia and precursor-related neoplasms: changes and unsolved issues. Falini B, Tiacci E, Martelli MP, Ascani S, Pileri SA. Discov Med. 2010 Oct;10(53):281-92. PMID: 21034669

- Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Kanezaki R, Toki T, Terui K, Xu G, Wang R, Shimada A, Hama A, Kanegane H, Kawakami K, Endo M, Hasegawa D, Kogawa K, Adachi S, Ikeda Y, Iwamoto S, Taga T, Kosaka Y, Kojima S, Hayashi Y, Ito E. Blood. 2010 Aug 20. PMID: 20729467