Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7

Furlan, Ingrid; Batz, Christiane; Flotho, Christian; Mohr, Brigitte; Lübbert, Michael; Suttorp, Meinolf; Niemeyer, Charlotte M.

doi:10.1182/blood-2008-12-195693

Cited by 67 publications

(49 citation statements)

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“…‡From the end of azacitidine treatment to death or last follow-up. §This case was published previously by Furlan et al 5 ||The patient reached genetic CR with disappearance of monosomy 7 and KRAS mutation after 5 and 7 cycles, respectively. Monosomy 7 was tested by fluorescence in situ hybridization, and KRAS mutation was assessed by Sanger sequencing.…”

supporting

confidence: 58%

“…We previously published the first case report of a boy with JMML who achieved a complete clinical and genetic remission after 8 cycles of azacitidine. 5 Here, we present a retrospective compilation of 12 children with JMML who received individual off-label treatment with azacitidine before HSCT (N 5 9) or for relapsed disease (N 5 3).…”

mentioning

confidence: 99%

“…One case (D644) was published previously. 5 The diagnosis of all children was centrally reviewed, and response was evaluated according to international consensus criteria. 6 The median age of the 12 patients was 4.8 years (range 0.4-9.1) ( Table 1).…”

mentioning

confidence: 99%

“…The third leukemia carried a somatic KRAS mutation, which was no longer detectable after 7 cycles of azacitidine (D644). 5 One child (CH058) experienced considerable regression of spleen size and became transfusion independent (scored as clinical PR). All 4 children underwent HSCT after 7 to 11 cycles.…”

mentioning

confidence: 99%

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Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

Cseh

Niemeyer

Yoshimi

et al. 2015

Blood

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confidence: 58%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

Cseh

Niemeyer

Yoshimi

et al. 2015

Blood

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“…99 A number of children have been treated off label since, 100 and a phase II study was recently initiated in Europe.…”

Section: Treatment Other Than Stem Cell Transplantationmentioning

confidence: 99%

RAS diseases in children

Niemeyer

2014

Haematologica

127

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REVIEW ARTICLES 1653 IntroductionDiscoveries made about 50 years ago revealed the transforming power of the Harvey and Kirsten murine sarcoma retroviruses by a set of genes named RAS genes for their role in forming rat sarcomas. Subsequently, the contribution of RAS genes to cancer pathogenesis has been studied extensively. While the somatic dysregulation of RAS is a primary driver of cancer, there is a class of developmental disorders caused by germline mutations (as opposed to the somatic mutations found in cancer) in genes that encode components of the RAS signaling pathway. This chapter summarizes hematologic disturbances and cancer predisposition of these genetic disorders named "RASopathies". It will focus on juvenile myelomonocytic leukemia (JMML), an infant leukemia with initiating germline and somatic mutations in genes of the RAS signal transduction pathway. RAS and the RAS/mitogen-activated protein kinase signaling cascadeRAS turned out to be an essential cellular hub for a wide variety of signaling pathways including the three human RAS genes, KRAS, NRAS and HRAS (reviewed by Stephen et al. 1). RAS proteins act as molecular switches by cycling between an active guanosine triphospate (GTP)-bound (RAS-GTP) and an inactive guanosine diphosphate (GDP)-bound (RAS-GDP) conformation (Figure 1).2 RAS-GTP concentrations are tightly regulated by the competitive action of guanosin exchange factors (GEFs) and GTPase activating proteins (GAPs).RAS is activated by extracellular stimuli such as growth factor binding to receptor tyrosine kinases (RTKs) followed by RTK autophosphorylation and the creation of docking sites for adaptor molecules (e.g. GRB2). These molecules recruit and activate GEFs (e.g. SOS1) which displace GDP from RAS allowing RAS to bind to GTP. RAS-GTP binds to and activates a large number of effector pathways. The RAS-mediated mitogen-activated kinase (MAPK) pathway is one of several important downstream cascades. Activated RAS binds to RAF (RAF1, also known as CRAF, BRAF), the first MAPK of the signaling cascade. RAF phosphorylates MEK1 and/or MEK2, which in turn activate ERK1 and/or ERK2. Active ERKs serve as regulators of a large number of downstream processes both in the cytosol and nucleus.

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Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia

Niemeyer

Locatelli

2015

Thomas’ Hematopoietic Cell Transplantation

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Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7

Cited by 67 publications

References 5 publications

Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group

RAS diseases in children

Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia

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