Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome

doi:10.1016/j.siny.2012.02.010

Seminars in Fetal and Neonatal Medicine

Volume 17, Issue 4, August 2012, Pages 196-201

https://doi.org/10.1016/j.siny.2012.02.010 Get rights and content

Summary

Children with Down syndrome (DS) have an increased risk of Acute Myeloid Leukaemia (ML-DS), particularly megakaryoblastic leukaemia, which is clonally -related to the neonatal myeloproliferative syndrome, Transient Abnormal Myelopoiesis (TAM) unique to infants with DS. Molecular, biological, and clinical data indicate that TAM is initiated before birth when fetal liver haematopoietic cells trisomic for chromosome 21 acquire mutations in GATA1. TAM usually resolves spontaneously by 6 months; however 20–30% subsequently develop ML-DS harbouring the same GATA1 mutation(s). This review focuses on recent studies describing haematological, clinical and biological features of TAM and discusses approaches to diagnose, treat and monitor minimal residual disease in TAM. An important unanswered question is whether ML-DS is always preceded by TAM as it may be clinically and possibly haematologically ‘silent’. We have briefly discussed the role of population-based screening for TAM and development of treatment strategies to eliminate the preleukaemic TAM clone, thereby preventing ML-DS.

Introduction

Infants with Down syndrome (DS; trisomy 21, T21) are at risk of developing a transient myeloproliferative disorder (TMD) in the neonatal period that is also known as Transient Abnormal Myelopoiesis (TAM) or Transient Leukaemia (TL). TAM is defined as a transient clonal myeloproliferation and is characterised by circulating megakaryoblasts in the peripheral blood. TAM is unique to neonates with DS or those with T21 mosaicism. Although TAM is estimated to occur in 4–10% of neonates with DS,1, 2, 3 its exact frequency is unknown as it may be clinically silent and full blood counts (FBC) and films are not routinely performed in most DS neonates. Several lines of evidence indicate that TAM develops in utero, that it originates in fetal liver haematopoietic cells and that it spontaneously resolves within months of birth as haematopoiesis in fetal liver ceases and switches to bone marrow.3, 4, 5, 6 Acquired mutations of the key megakaryocyte transcription factor GATA1 have been identified in blasts of almost all cases of TAM, providing important insight into their pathogenesis.7, 8, 9, 10 Identifying TAM in the neonatal period is important since 20–30% of cases later transform to Acute Myeloid Leukaemia (ML-DS).4, 5, 11 There are several uncertainties about the diagnosis, natural history, pathogenesis and optimum management of the disease, including the usefulness of screening to determine the true incidence of TAM; the best criteria to diagnose TAM; which neonates warrant treatment and the best treatment protocol; whether or not treatment can prevent future ML-DS; and whether a mutant leukaemic subclone that persists after resolution of TAM reappears as ML-DS and how best to monitor the disease. This review outlines the haematological and biological features of TAM and how recent advances in our understanding of the molecular pathogenesis of this condition may help in diagnosing, treating and monitoring the disease.

Section snippets

Clinical features of TAM

TAM has a variable presentation in the fetus and the newborn from mild disease to disseminated leukaemic infiltration and fulminant hepatic fibrosis.3, 4, 5, 6 Data from recent prospective studies found a median age at diagnosis of TAM of 3-7 days and almost all cases presented within 2 months of birth.4, 5, 6, 11 Approximately 10–25% of newborns are asymptomatic4, 5 and present with circulating blast cells, with or without leucocytosis. Babies with clinical symptoms most commonly present with

Haematology

TAM is characterised by several haematological abnormalities including:

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Leucocytosis, with ∼20–30% cases having high WBC counts (>100 × 10⁹/L),4, 11 although WBC counts may be normal.
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Abnormal platelet count (thrombocytopenia in ∼40% of cases)
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Haemoglobin may be normal, reduced or raised.
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Abnormal coagulation (∼22%) or disseminated intravascular coagulation (DIC; ∼7%)4, 11
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Increased peripheral blood blasts, usually with megakaryoblastic morphology (Fig. 1).

Myeloid blasts in the peripheral blood with

Natural history of TAM

Most neonates with TAM (>80%) do not need treatment as the clinical and laboratory abnormalities spontaneously resolve within 3-6 months after birth.4, 5, 11 Five year overall survival is ∼80% and event-free survival ∼60%.4, 11 Overall mortality is∼20%, however the case fatality rate (deaths directly attributed to TAM) is ∼10%.4, 5, 11 In most studies all neonates presenting with liver fibrosis died. Several other factors are associated with an increased risk of death, namely preterm delivery,

Management of TAM

Although, as mentioned above, most babies with TAM do not need treatment, outcome for those who have progressive, life-threatening signs such as hepatic, renal and/or cardiac failure, may be improved by administration of one or more short courses of low-dose cytosine arabinoside. An important dilemma in the management of TAM is identifying which infants will benefit from treatment and what treatment is most effective in the short- and long-term. This remains unclear since diagnostic criteria

Molecular basis of TAM

TAM and ML-DS are linked clonal conditions with a distinct pathogenetic basis tightly linked to trisomy 21 - TAM only occurs in neonates with DS or with trisomy 21 in their haematopoietic cells (mosaic DS). Haematopoietic cells in TAM and ML-DS are uniquely marked by the presence of acquired, N-terminal truncating mutations in the GATA17, 8, 10, 23, 24, 25 which occur at high frequency in DS neonates (4–10% of all DS neonates2, 3, 7). Importantly, similar N-terminal GATA1 mutations, in the

Conclusions

TAM and ML-DS provide fascinating insights into the steps by which fetal HSC/progenitors are transformed and the role of trisomy 21 in this process (Fig. 2). Identification of GATA1 mutations in virtually all cases of TAM offers the potential to refine the diagnosis of TAM, and to accurately measure minimal residual disease. The true incidence of TAM is difficult to determine without prospectively screening all DS neonates, which is currently underway in the Oxford Imperial DS Cohort Study,

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Transient abnormal myelopoiesis with extramedullary involvement in a down syndrome preemie leading to an unresponsive course despite chemotherapy
2023, Leukemia Research Reports
Transient abnormal myelopoiesis (TAM) is a transient, clonal myeloproliferative disorder unique to Down Syndrome (DS) babies. It is characterized by increased peripheral blasts and presence of GATA1 mutation. The clinical spectrum ranges from jaundice and hepatosplenomegaly to multi-organ failure and death. Here we present a case of a premature baby with DS diagnosed to have TAM with extramedullary involvement at birth who had a fatal outcome.
A 30.3-week-old female fetus with DS had leukocytosis (WBC: 187.82 K/uL) with neutrophilia (ANC 27.65 K/uL), macrocytic anemia (RBC: 2.41 m/uL, Hb 8.8 g/dL, MCV 108.3, MCH 36.5, MCHC 33.7) and thrombocytosis (platelet count 361 K/uL) at birth. Liver panels demonstrated normal bilirubin levels with elevated liver enzymes (AST = 239 U/L, ALT = 216 U/L).
Peripheral smear showed marked leukocytosis with increased blasts (70%), nucleated RBCs, giant platelets, and megakaryocytic elements. Flow cytometry demonstrated two populations of cells: 20% myeloblasts and 26% dim CD45 CD34- cells. GATA1 mutation was present. Based on these findings a diagnosis of TAM with extramedullary hematopoiesis was made. She received two cycles of cytarabine chemotherapy. Though her WBC levels reached a low of 18.93 K/uL, she developed multi-organ failure, eventually leading to death on day 45.
TAM is a transient condition resulting in disease resolution in around 80% of cases. Death is reported in 10% of cases. Risk factors associated with early death include prematurity, hyperleukocytosis, elevated bilirubin levels. Management of high-risk babies with chemotherapy is recommended to improve survival.
Precision medicine in myeloid malignancies
2022, Seminars in Cancer Biology
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Like in MDS, the molecular pathogenesis of AML is based on the subsequent acquisition of somatic mutations in the compartment of myeloid progenitors, comprising HSCs and their more mature descendants [3,28]. AML with familial disposition and myeloid proliferations of Down syndrome are reviewed elsewhere [152–154]. According to the classical model of AML pathogenesis, evolution of AML is determined by at least two functionally different classes of mutations, which either provide proliferative advantage or which alter differentiation of HSCs [155,156].
Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) “Achilles heels” that can further improve myeloid cancer therapy.
Profile of down syndrome–associated malignancies: Epidemiology, clinical features and therapeutic aspects
2021, Pediatric Hematology Oncology Journal
Down syndrome (DS) is a congenital chromosomal abnormality caused by the presence of all or part of a third copy of chromosome 21 (+21). DS is frequently complicated by congenital heart or digestive tract diseases at birth. DS patients are prone to infections and have mental retardation, with dementia such as Alzheimer's disease showing in later life. Furthermore, malignancies with specific characteristics are also highly reported in DS patients compared with non-DS patients. Therefore, DS is believed to be a cancer predisposition syndrome due to the chromosomal instability. Acute myeloid leukemia (AML) and especially acute megakaryoblastic leukemia (AMKL) by French-American-British (FAB) classification are the most frequent hematological malignancies in DS patients, occurring at a rate that is 500 times higher than that in non-DS patients. Interestingly, transient abnormal myelopoiesis (TAM) is observed in approximately 10% of DS neonates with GATA1 mutations, and most TAM patients are asymptomatic and show spontaneous regression; however, about 10%–20% of TAM cases are fatal because of complications such as fetal effusion, liver fibrosis, and other complications.
Acute lymphoblastic leukemia (ALL) is also associated with DS, occurring at a rate that is 20 times higher than that in non-DS patients. Furthermore, the prognosis of DS-ALL patients is poorer than that of non-DS-ALL patients. A recent genetic analysis revealed that more than half of DS-ALL cases have a mutation in the CRLF2–JAK pathway, indicating that JAK inhibitors might have a limited effect for DS-ALL patients.
Notably, solid tumors such as neuroblastoma, Wilms tumor, and brain tumor, which are frequently observed in non-DS children, are rarely reported in DS children. The reason remains unknown, but it may be because of the triplication of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21. In adult patients with DS, the expected age-adjusted incidence rates of solid tumors are low compared with age-matched euploid cohorts for most cancers except for testicular cancer. Although the average life expectancy of patients with DS will increase with advances in healthcare, the detailed health problems including cancer rates in older DS patients remain unknown. Therefore, these issues will be needed to be addressed in future studies.
The in vitro effects of hepatoblastoma cells on the growth and differentiation of blasts in transient abnormal myelopoiesis associated with Down syndrome
2021, Leukemia Research
Citation Excerpt :
This disorder is considered to be a special form of self-limiting leukemia or a preleukemic syndrome, and a variety of terms have been used for this disorder, including transient abnormal myelopoiesis (TAM), transient myeloproliferative disorder and transient leukemia [2–7]. Although the prognosis of patients with TAM is generally good, fatal organ failure may develop in up to 20 % of patients due to leukemic cell infiltration or other complications [7,8], and 20–30 % of cases of TAM progress to non-remitting AMKL-DS after spontaneous remission by the age of 4 years [1]. Somatic mutations affecting the GATA1 gene, which encodes a member of the GATA family of zinc-finger transcription factors, have been detected exclusively in TAM and AMKL-DS in nearly all cases [9–11].
Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome, which spontaneously resolves within several weeks or months after birth, may represent a special form of leukemia developing in the fetal liver (FL). To explore the role of hepatoblasts, one of the major constituents of the FL hematopoietic microenvironment, in the pathogenesis of TAM, we investigated the influence of a human hepatoblastoma cell line, HUH-6, on the in vitro growth and differentiation of TAM blasts. In a coculture system with membrane filters, which hinders cell-to-cell contact between TAM blasts and HUH-6 cells, the growth and megakaryocytic differentiation of TAM blast progenitors were increased in the presence of HUH-6 cells. The culture supernatant of HUH-6 cells contained hematopoietic growth factors, including stem cell factor (SCF) and thrombopoietin (TPO). The neutralizing antibody against SCF abrogated the growth-stimulating activity of the culture supernatant of HUH-6 cells, demonstrating that, among the growth factors produced by HUH-6 cells, SCF may be the major growth stimulator and that TPO may be involved in megakaryocytic differentiation, rather than growth, of TAM blasts. This suggests that hepatoblasts function in the regulation of the growth and differentiation of TAM blasts in the FL through the production of hematopoietic growth factors, including SCF and TPO, and are involved in the leukemogenesis of TAM.
Neonatal Leukemia
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Of the 6000 or so babies born each year with DS (constitutional trisomy 21) in the United States, approximately 10% to 15% develop TAM.45 The clinical presentation of TAM varies tremendously, from an asymptomatic condition, detected only as an incidental finding due to abnormal blood counts, to a critical illness, with massive hepatosplenomegaly with jaundice and transaminase elevation, pleural/pericardial effusions, coagulopathy, and multiorgan failure due to widespread leukemic infiltration.46,47 Blood count abnormalities (high WBC counts and low platelets, anemia) and circulating megakaryoblasts are among the most common signs, so it is essential to review a peripheral blood smear for all neonates with DS.48
Myeloid Proliferations of Down Syndrome
2018, Atlas of Hematopathology: Morphology, Immunophenotype, Cytogenetics, and Molecular Approaches, Second Edition
Patients with Down syndrome (DS) (trisomy of chromosome 21) have a 10- to 20-fold higher relative risk for leukemia. Approximately 10% of neonates with DS develop a transient abnormal myelopoiesis (TAM), which regresses spontaneously in the vast majority of the cases. However, about 20% of the affected neonates will eventually develop AML before age 5. The vast majority of the AML cases in DS patients are of megakaryoblastic subtype. Both TAM and DS-related megakaryoblastic leukemia are associated with the GATA-1 mutations.

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Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome

Summary

Introduction

Section snippets

Clinical features of TAM

Haematology

Natural history of TAM

Management of TAM

Molecular basis of TAM

Conclusions

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Leuk Res

Blood

Blood

Blood

Lancet

J Pediatr

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England

J Clin Pathol

Transient leukaemia–a benign form of leukaemia in newborn infants with trisomy 21

Br J Haematol