Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation

Choi, Sung Won; Boxer, Laurence A.; Pulsipher, Mike A.; Roulston, Diane; Hutchinson, Raymond J.; Yanik, Greg; Cooke, Kenneth R.; Ferrara, James L.M.; Levine, John E.

doi:10.1038/sj.bmt.1704813

Cited by 45 publications

(44 citation statements)

References 29 publications

(28 reference statements)

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“…outcomes of transplantation in this group that might be weighed against the risks of sepsis death or MDS/AML described here. From the limited transplantation data, it appears that SCN patients should receive transplants prior to the onset of MDS/AML, 35,36 and that results using matched sibling donors may be superior to those from alternative donors. [35][36][37] Until further experience is accumulated, the decision to use this potentially curative modality must be individualized, and preferably performed at a transplantation center with protocols for SCN patients.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy

Rosenberg

Alter

Bolyard³

et al. 2006

Blood

384

287

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Section: Discussionmentioning

confidence: 99%

“…Our results suggest that less-responsive patients, in particular, should adhere to recommendations for bone marrow examination at least annually. 35 Recent protocols incorporating conscious sedation should make these evaluations less trying for patients and their families.…”

Section: Discussionmentioning

confidence: 99%

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy

Rosenberg

Alter

Bolyard³

et al. 2006

Blood

384

287

View full text Add to dashboard Cite

“…58,76 Regular monitoring of CSF3R mutations has been considered to be helpful to screen for the risk of leukemic transformation, 58 but when CSF3R mutations are present in minor clones, they can easily be missed in direct sequencing protocols. Possibly, next-generation sequencing technologies allowing mutation detection in smaller subsets of cells will resolve this problem.…”

Section: Are Csf3r Mutations Useful Predictors For Leukemic Progressimentioning

confidence: 99%

G-CSF and its receptor in myeloid malignancy

Beekman

Touw

2010

Blood

151

115

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Granulocyte colony-stimulating factor (G-CSF) has been used in the clinic for more than 2 decades to treat congenital and acquired neutropenias and to reduce febrile neutropenia before or during courses of intensive cytoreductive therapy. In addition, healthy stem cell donors receive short-term treatment with G-CSF for mobilization of hematopoietic stem cells. G-CSF has also been applied in priming strategies designed to enhance the sensitivity of leukemia stem cells to cytotoxic agents, in protocols aimed to induce their differentiation and accompanying growth arrest and cell death, and in severe aplastic anemia and myelodysplastic syndrome (MDS) to alleviate anemia. The potential adverse effects of G-CSF administration, particularly the risk of malignant transformation, have fueled ongoing debates, some of which can only be settled in follow-up studies extending over several decades. This specifically applies to children with severe congenital neutropenia who receive lifelong treatment with G-CSF and in which the high susceptibility to develop MDS and acute myeloid leukemia (AML) has now become a major clinical concern. Here, we will highlight some of the controversies and chal- G-CSF and its receptorThe growth factor granulocyte colony-stimulating factor (G-CSF), now referred to as CSF3, is the major regulator of neutrophil production under basal conditions of hematopoiesis, as is evident from the fact that CSF3 or CSF3 receptor-deficient mice are severely neutropenic. 1,2 CSF3 is also essential for "emergency" granulopoiesis in response to bacterial infections and enhances multiple neutrophil functions. 3 CSF3 exerts its role by inducing proliferation and survival of myeloid progenitor cells, followed by a cell-cycle arrest and neutrophilic differentiation. 4 The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. When CSF3R mutants were expressed in differentiation competent factor-dependent myeloid cell lines, the distal cytoplasmic region of the CSF3R of approximately 100 amino acids was crucial for CSF3-induced neutrophilic differentiation of these cells. 5 Although originally being considered as "differentiation domain," later studies demonstrated that this C-terminal region exerts a negative role in STAT5 activation and proliferation signaling in vivo. 6,7 Negative regulators of CSF3 signaling linked to the distal C-terminus of CSF3R include the protein tyrosine phosphatases SHP-1 and the suppressor of cytokine signaling (SOCS) protein SOCS3. The SOCS protein family is characterized by a so-called SOCS box, a domain involved in the recruitment of ubiquitin (E3) ligase activity. The negative action of SOCS3 and more specifically of its SOCS box on CSF3 signaling has been demonstrated in conditional knockout models. 8,9 A mechanism for receptor down-regulation has been proposed in which SOCS3 drives ubiquitination of a conserved ju...

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“…24 However, a later study did not support this idea. 6 Because current therapies, including those involving allogeneic HSC transplantation, fail to cure SCN/AML, 25,26 it is important to consider adaptations in the treatment before malignant transformation occurs. Notably, rare cases progressing to ALL or CMML have also been reported.…”

Section: Leukemic Transformation Of Scn and Xlnmentioning

confidence: 99%

Game of clones: the genomic evolution of severe congenital neutropenia

Touw

2015

Hematology

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Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue. These days, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). CSF3 therapy has greatly improved the life expectancy of SCN patients, but also unveiled a high frequency of progression toward myelodysplastic syndrome (MDS) and therapy refractory acute myeloid leukemia (AML). Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones. These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia. The vast (sub)clonal heterogeneity of AML and the presence of AML-associated mutations in normally aged hematopoietic clones make it often difficult to determine which mutations are responsible for the leukemic process. Leukemia predisposition syndromes such as SCN are unique disease models to identify the sequential acquisition of these mutations and to interrogate how they contribute to clonal selection and leukemic evolution. Learning Objectives• Knowledge of the possible mechanisms by which mutations in ELANE or HAX1 cause SCN and the controversies that preclude a unifying hypothesis • Understanding of how somatic mutations in CSF3R affect CSF3-induced signal transduction and contribute to the expansion of hematopoietic clones in SCN

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Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation

Cited by 45 publications

References 29 publications

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy

G-CSF and its receptor in myeloid malignancy

Game of clones: the genomic evolution of severe congenital neutropenia

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