Myeloid leukemia in Prader-Willi syndrome

Davies, H. Dele; Leusink, Geraline L; McConnell, Athena; Deyell, Marc W.; Cassidy, Suzanne B.; Fick, Gordon H.; Coppes, Max J.

doi:10.1067/mpd.2003.81

Cited by 50 publications

(34 citation statements)

References 30 publications

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“…[26][27][28] It has recently been reported that patients with Prader-Willi syndrome have a 40 times higher incidence of myeloid leukemia than normal persons. 50 Although our Ndn-deficient mice did not develop leukemia under normal conditions, it is possible, given the elevated proliferation of HSCs in Ndn-deficient mice, that necdin deficiency might contribute to the development of leukemia. Hence, in this regard, more future studies of Ndn-deficient mice are desirable to determine whether there is any correlation between necdin deficiency and leukemia.…”

Section: Discussionmentioning

confidence: 99%

Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration

Kubota¹,

Osawa

Jakt³

et al. 2009

Blood

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Hematopoietic stem cell (HSC) proliferation is tightly regulated by a poorly understood complex of positive and negative cell-cycle regulatory mechanisms. Necdin (Ndn) is an evolutionally conserved multifunctional protein that has been implicated in cell-cycle regulation of neuronal cells. Here, we provide evidence that necdin plays an important role in restricting excessive HSC proliferation during hematopoietic regeneration. We identify Ndn as being preferentially expressed in the HSC population on the basis of gene expression profiling and demonstrate that mice deficient in Ndn show accelerated recovery of the hematopoietic system after myelosuppressive injury, whereas no overt abnormality is seen in steady-state hematopoiesis. In parallel, after myelosuppression, Ndn-deficient mice exhibit an enhanced number of proliferating HSCs. Based on these findings, we propose that necdin functions in a negative feedback loop that prevents excessive proliferation of HSCs during hematopoietic regeneration. These data suggest that the inhibition of necdin after clinical myelosuppressive treatment (eg, chemotherapy, HSC transplantation) may provide therapeutic benefits by accelerating hematologic recovery. (Blood. 2009;114:4383-4392)

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Section: Discussionmentioning

confidence: 99%

Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration

Kubota¹,

Osawa

Jakt³

et al. 2009

Blood

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“…63 The gene encoding Necdin is one of several genes that are deleted in individuals with Prader-Willi syndrome, a disorder associated with an increased risk of myeloid leukemia. 64 Like the retinoblastoma protein, Necdin interacts with multiple cell cycle promoting proteins such as simian virus 40 large T antigen, adenovirus E1A and the transcription factor E2F1. 65-67 We, and others, have shown that Necdin is highly expressed in LT-HSCs, 1,21 and while its role in hematopoiesis is largely unknown, we have demonstrated that the enhanced quiescence exhibited by Mef null HSCs is at least in part mediated by Necdin.…”

Section: Introductionmentioning

confidence: 99%

The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior

et al. 2009

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In response to diverse stresses, the tumor suppressor p53 differentially regulates its target genes, variably inducing cell cycle arrest, apoptosis or senescence. Emerging evidence indicates that p53 plays an important role in regulating hematopoietic stem cell (HSC) quiescence, self-renewal, apoptosis and aging. The p53 pathway is activated by DNA damage, defects in ribosome biogenesis, oxidative stress and oncogene induced p19ARF upregulation. We present an overview of the current state of knowledge about p53 (and its target genes) in regulating HSC behavior, with the hope that understanding the molecular mechanisms that control p53 activity in HSCs and how p53 mutations affect its role in these events may facilitate the development of therapeutic strategies for eliminating leukemia (and cancer) propagating cells.

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“…Our finding of a specific association of leukemia in mothers of infants in the very high birth weight category rather than a continuous relation with increasing birthweight raises questions regarding specific macrosomic phenotypes and their relation to maternal leukemia. Beckwith-Wiedemann, and Prader Willi syndromes are disorders related to excessive growth, uniparental disomy and abnormal imprinting [28,29]; both syndromes have been associated with leukemia in affected individuals [30][31][32][33][34], but have not been reported with maternal cancer. We excluded parents of children with congenital anomalies, which have themselves been reported as risk factors for leukemia [35].…”

Section: Discussionmentioning

confidence: 99%

Very high birth weight of offspring is associated with an increased risk of leukemia in their mothers: Results of a population-based cohort study

et al. 2008

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Although the association between birthweight and childhood leukemia is well-described, the relation between a child's birthweight and parental risk of leukemia is unknown. We linked data from the Jerusalem Perinatal study to the Israel Cancer Registry to ascertain the incidence of leukemia in mothers and fathers in relation to their offspring's birthweight. Birthweight ≥4500 gm in any of the offspring was associated with a >3-fold risk of leukemia in mothers, but not fathers. Potential mechanisms include shared exposures of high-birthweight infants and their mothers, possibly to radiation or growth factors, or genetic pathways leading to both high birthweight and leukemia.

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Myeloid leukemia in Prader-Willi syndrome

Cited by 50 publications

References 30 publications

Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration

Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration

The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior

Very high birth weight of offspring is associated with an increased risk of leukemia in their mothers: Results of a population-based cohort study

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