Evolution of myeloid leukemia in children with Down syndrome

Abstract

the general population, the distribution of malignancies is different [3]. Patients with DS show a unique spectrum of malignancies, with a 10-to 20-fold higher risk of acute leukemia and a lower incidence of solid tumors [3,4]. Death from malignancies other than leukemia is strikingly less common in patients of all ages in DS, and death from leukemia is more likely in children younger than 10 years of age with DS than in those without [5]. The most frequent form of leukemia during childhood, both with and without DS, is acute lymphoblastic leukemia (ALL), and the incidence of ALL in children with DS is approximately 20-fold higher than in non-DS children [3]. However, the most marked increase in incidence in DS infants is with acute megakaryoblastic leukemia (AMKL), a myeloid malignancy of platelet precursors. The relative risk of developing AMKL is estimated to be 500 times higher in children with DS than in the general population [6]. Unlike AMKL in non-DS patients, most AMKL associated with DS (DS-AMKL) patients usually respond well to chemotherapy.In most cases, DS-AMKL is preceded by a temporary form of megakaryoblastic leukemia unique to newborns with DS and known as transient abnormal myelopoiesis (TAM) or transient leukemia. TAM, a clonal myeloproliferative syndrome, presents in the fetus or a few days after birth and in most cases resolves spontaneously within 3 months [7,8]. Typically, TAM is characterized by the presence of high numbers of circulating blast cells expressing CD33, CD38, CD117, CD34, CD7, CD56, CD36, CD71, and CD42b [9], which are indistinguishable from blasts observed in DS-AMKL. More often, the clinical presentation of TAM varies from asymptomatic alterations in the blood count to disseminated leukemic infiltration. Clinically severe TAM (liver failure, pleural/pericardial effusion, ascites, renal failure, and coagulopathy) affects 10-30 % of patients with clinically diagnosed TAM, and Abstract Children with Down syndrome (DS) have a markedly increased risk of leukemia. They are at particular risk of acute megakaryoblastic leukemia, known as myeloid leukemia associated with DS (ML-DS), the development of which is closely linked to a preceding temporary form of neonatal leukemia called transient abnormal myelopoiesis (TAM). Findings from recent clinical and laboratory studies suggest that constitutional trisomy 21 and GATA1 mutation(s) cause TAM, and that additional genetic alteration(s) including those in epigenetic regulators and signaling molecules are involved in the progression from TAM to ML-DS. Thus, this disease progression represents an important model of multi-step leukemogenesis. The present review focuses on the evolutionary process of TAM to ML-DS, and advances in the understanding of perturbed hematopoiesis in DS with respect to GATA1 mutation and recent findings, including cooperating genetic events, are discussed.

Modeling Transient Abnormal Myelopoiesis Using Induced Pluripotent Stem Cells and CRISPR/Cas9 Technology

“… 1 Young children with DS have a 500-fold increased incidence of acute myeloid leukemia (AML), 2 probably because of the imbalance in the expression of genes, such as RUNX1 , DYRK1A on chromosome 21, which can affect hematopoiesis. 3 , 4 A 4-Mb region on chromosome 21 containing transcription factors RUNX1 , ETS2 , and ERG was shown to be sufficient for transient abnormal myelopoiesis (TAM) in the presence of a GATA1 mutation. 5 Specifically, 1%–2% of DS children develop AML prior to age 5 years.…”

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

“…After remission, approximately 20% of patients with TAM develop acute myeloid leukemia (AML) associated with Down syndrome (ML‐DS) . Given that blasts in both TAM and ML‐DS have common genetic abnormalities, including trisomy 21 and GATA binding protein 1 ( GATA1 ) mutation, TAM is considered a pre‐leukemic disorder, and understanding how TAM progresses to ML‐DS may provide information crucial to clarifying the mechanism involved in multi‐step leukemogenesis . Recent studies using a xenograft model and next‐generation sequencing (NGS) have detected subclones that emerge during the TAM phase and appear to expand to develop into overt leukemia through clonal selection and additional genetic alterations …”

“…2,3,5,6 Given that blasts in both TAM and ML-DS have common genetic abnormalities, including trisomy 21 and GATA binding protein 1 (GATA1) mutation, 7-13 TAM is considered a pre-leukemic disorder, and understanding how TAM progresses to ML-DS may provide information crucial to clarifying the mechanism involved in multi-step leukemogenesis. [14][15][16][17] Recent studies using a xenograft model and next-generation sequencing (NGS) have detected subclones that emerge during the TAM phase and appear to expand to develop into overt leukemia through clonal selection and additional genetic alterations. 18,19 This review outlines the clinical features of TAM and focuses on the latest findings that may provide clues to the understanding of this unique disease.…”

Children with Down Syndrome and Leukemia in Kuwait-Experience of the only Pediatric Hematology Oncology Department in Kuwait

“…AMkL is the most common French-American-British subtype of DS AML patients, as reported to represent more than 90% of DS AML cases. The majority of cases are diagnosed before the age of 4 years [14,15], and uniformly harbor somatic mutations in the transcription factor GATA1 gene [16]; however we have seen DS children with different types of AML in this study. The other AML French-American-British subtypes described in DS AML including M0, M1/M2, and M6 [17].…”