Top

Published in:

01-06-2012 | Current Opinion

Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations

Authors: Nao Yoshida, Sayoko Doisaki, Dr Seiji Kojima

Published in: Pediatric Drugs | Issue 3/2012

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myelodysplastic/myeloproliferative disorder that affects young children. It is characterized by hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. The pathogenesis of JMML seems to arise from constitutional activation of the GM-CSF/RAS (a GTPase) signaling pathway, a result of mutations in RAS, NF1, PTPN11, and CBL that interfere with downstream components of the pathway. Most patients with JMML usually experience an aggressive clinical course, and hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment, although the high rates of relapses and graft failures are of great concern. In contrast, a certain proportion of patients experience a stable clinical course for a considerable period of time, and sometimes the disease even spontaneously resolves without any treatment.

Recent studies have provided us with increased knowledge of genotype-phenotype correlations in JMML, and suggested that differences in clinical courses may reflect genetic status. Thus, genotype-based management is of current international interest, especially for JMML with RAS mutations. Cumulative evidence suggests that RAS mutations can be related to favorable clinical outcomes, and HSCT may not have to be a mandatory therapeutic option for a portion of patients with this mutation, although a consensus regarding genotype-based management has not yet been achieved. Further efforts toward identifying which patients who will do well without HSCT are required.

Jaffe ES, Harris NL, Stein H, et al. WHO classification of tumors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press, 2001.

Emanuel PD, Bates LJ, Castleberry RP, et al. Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 1991 Mar 1; 77 (5): 925–9.PubMed

Side LE, Emanuel PD, Taylor B, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 1998 Jul 1; 92 (1): 267–72.PubMed

Flotho C, Valcamonica S, Mach-Pascual S, et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 1999 Jan; 13 (1): 32–7.PubMedCrossRef

Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003 Jun; 34 (2): 148–50.PubMedCrossRef

Loh ML, Sakai DS, Flotho C, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 2009 Aug 27; 114 (9): 1859–63.PubMedCrossRef

Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 1997 May 15; 89 (10): 3534–43.PubMed

Niemeyer CM, Fenu S, Hasle H, et al. Differentiating juvenile myelomonocytic leukemia from infectious disease [reply]. Blood 1998; 91 (1): 365–7.

Manabe A, Yoshimasu T, Ebihara Y, et al. Viral infections in juvenile myelomonocytic leukemia: prevalence and clinical implications. J Pediatr Hematol Oncol 2004 Oct; 26 (10): 636–41.PubMedCrossRef

10.

Chan RJ, Cooper T, Kratz CP, et al. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 2009 Mar; 33 (3): 355–62.PubMedCrossRef

11.

deVries AC, Zwaan CM, van denHeuvel-Eibrink MM. Molecular basis of juvenile myelomonocytic leukemia. Haematologica 2010 Feb; 95 (2): 179–82.PubMedCrossRef

12.

Emanuel PD. RAS pathway mutations in juvenile myelomonocytic leukemia. Acta Haematol 2008; 119 (4): 207–11.PubMedCrossRef

13.

Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 1990 Nov 8; 348 (6297): 125–32.PubMedCrossRef

14.

deVries AC, Stam RW, Kratz CP, et al. Mutation analysis of the BRAF oncogene in juvenile myelomonocytic leukemia. Haematologica 2007 Nov; 92 (11): 1574–5.PubMedCrossRef

15.

Kratz CP, Niemeyer CM, Thomas C, et al. Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia. Leukemia 2007 May; 21 (5): 1108–9.PubMed

16.

Zecca M, Bergamaschi G, Kratz C, et al. JAK2 V617F mutation is a rare event in juvenile myelomonocytic leukemia. Leukemia 2007 Feb; 21 (2): 367–9.PubMedCrossRef

17.

Yoshida N, Yagasaki H, Takahashi Y, et al. Mutation analysis of SIPA1 in patients with juvenile myelomonocytic leukemia. Br J Haematol 2008 Sep; 142 (5): 850–1.PubMedCrossRef

18.

Miyauchi J, Asada M, Sasaki M, et al. Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 1994 Apr 15; 83 (8): 2248–54.PubMed

19.

Xu GF, O’Connell P, Viskochil D, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 1990 Aug 10; 62 (3): 599–608.PubMedCrossRef

20.

Bader-Meunier B, Tchernia G, Mielot F, et al. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 1997 Jun; 130 (6): 885–9.PubMedCrossRef

21.

Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001 Dec; 29 (4): 465–8.PubMedCrossRef

22.

Hof P, Pluskey S, Dhe-Paganon S, et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell 1998 Feb 20; 92 (4): 441–50.PubMedCrossRef

23.

Muramatsu H, Makishima H, Jankowska AM, et al. Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 2010 Mar 11; 115 (10): 1969–75.PubMedCrossRef

24.

Perez B, Mechinaud F, Galambrun C, et al. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 2010 Oct; 47 (10): 686–91.PubMedCrossRef

25.

Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 2010 Sep; 42 (9): 794–800.PubMedCrossRef

26.

Schmidt MH, Dikic I. The Cbl interactome and its functions. Nat Rev Mol Cell Biol 2005 Dec; 6 (12): 907–18.PubMedCrossRef

27.

Zenker M, Lehmann K, Schulz AL, et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 2007 Feb; 44 (2): 131–5.PubMedCrossRef

28.

Niihori T, Aoki Y, Narumi Y, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 2006 Mar; 38 (3): 294–6.PubMedCrossRef

29.

Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006 Mar; 38 (3): 331–6.PubMedCrossRef

30.

Lo FS, Lin JL, Kuo MT, et al. Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature. Eur J Pediatr 2009 Aug; 168 (8): 919–23.PubMedCrossRef

31.

Kratz CP, Niemeyer CM, Zenker M. An unexpected new role of mutant Ras: perturbation of human embryonic development. J Mol Med 2007 Mar; 85 (3): 227–35.PubMedCrossRef

32.

Cirstea IC, Kutsche K, Dvorsky R, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 2010 Jan; 42 (1): 27–9.PubMedCrossRef

33.

DeFilippi P, Zecca M, Lisini D, et al. Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia. Br J Haematol 2009 Dec; 147 (5): 706–9.PubMedCrossRef

34.

Sarkozy A, Carta C, Moretti S, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat 2009 Apr; 30 (4): 695–702.PubMedCrossRef

35.

Fukuda M, Horibe K, Miyajima Y, et al. Spontaneous remission of juvenile chronic myelomonocytic leukemia in an infant with Noonan syndrome. J Pediatr Hematol Oncol 1997 Mar–Apr; 19 (2): 177–9.PubMedCrossRef

36.

Silvio F, Carlo L, Elena B, et al. Transient abnormal myelopoiesis in Noonan syndrome. J Pediatr Hematol Oncol 2002 Dec; 24 (9): 763–4.PubMedCrossRef

37.

Kratz CP, Niemeyer CM, Castleberry RP, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 2005 Sep 15; 106 (6): 2183–5.PubMedCrossRef

38.

Matsuda K, Shimada A, Yoshida N, et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 2007 Jun 15; 109 (12): 5477–80.PubMedCrossRef

39.

Manabe A, Okamura J, Yumura-Yagi K, et al. Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia 2002 Apr; 16 (4): 645–9.PubMedCrossRef

40.

Passmore SJ, Chessells JM, Kempski H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 2003 Jun; 121 (5): 758–67.PubMedCrossRef

41.

Locatelli F, Nollke P, Zecca M, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005 Jan 1; 105 (1): 410–9.PubMedCrossRef

42.

Niemeyer CM, Tartaglia M, Jung A, et al. Clinical characteristics of patients with JMML according to mutational status. Leukemia Research 2006; 30 Suppl. 2: S5.CrossRef

43.

Yoshida N, Yagasaki H, Xu Y, et al. Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res 2009 Mar; 65 (3): 334–40.PubMedCrossRef

44.

Flotho C, Kratz CP, Bergstrasser E, et al. Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. Blood 2008 Jan 15; 111 (2): 966–7; author reply 7–8.PubMedCrossRef

45.

Bresolin S, Zecca M, Flotho C, et al. Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol 2010 Apr 10; 28 (11): 1919–27.PubMedCrossRef

46.

Doisaki S, Muramatsu H, Hama A, et al. A favorable outcome in children with juvenile myelomonocytic leukemia (JMML) with RAS mutations. Blood 2010 Nov 19; 116 (21): 1197–8.

47.

Takagi M, Shinoda K, Piao J, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 2011 Mar 10; 117 (10): 2887–90.PubMedCrossRef

48.

Manabe A, Kojima S. 11th Symposium on Aplastic Anemia and 9th Symposium on Myelodysplastic Syndromes in Children. Pediatr Int 2005 Oct; 47 (5): 572–4.PubMedCrossRef

49.

Yabe M, Sako M, Yabe H, et al. A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant 2008 Dec; 12 (8): 862–7.PubMedCrossRef

50.

Yoshida N, Hirabayashi S, Watanabe S, et al. A prospective registration of children with juvenile myelomonocytic leukemia: follow-up of 75 patients. Rinsho Ketsueki 2011 Dec; 52 (12): 1853–8.PubMed

51.

Smith FO, King R, Nelson G, et al. Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 2002 Mar; 116 (3): 716–24.PubMedCrossRef

52.

Olk-Batz C, Poetsch AR, Nöllke P, et al. Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood 2011 May 5; 117 (18): 4871–80.PubMedCrossRef

53.

Yoshimi A, Niemeyer CM, Bohmer V, et al. Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia. Br J Haematol 2005 May; 129 (4): 542–9.PubMedCrossRef

54.

Archambeault S, Flores NJ, Yoshimi A, et al. Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia. Blood 2008 Feb 1; 111 (3): 1124–7.PubMedCrossRef

55.

Matsuda K, Sakashita K, Taira C, et al. Quantitative assessment of PTPN11 or RAS mutations at the neonatal period and during the clinical course in patients with juvenile myelomonocytic leukaemia. Br J Haematol 2010 Feb; 148 (4): 593–9.PubMedCrossRef

56.

Flotho C, Kratz C, Niemeyer CM. Targeting RAS signaling pathways in juvenile myelomonocytic leukemia. Curr Drug Targets 2007 Jun; 8 (6): 715–25.PubMedCrossRef

Title: Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations
Authors: Nao Yoshida
Sayoko Doisaki
Dr Seiji Kojima
Publication date: 01-06-2012
Publisher: Springer International Publishing
Published in: Pediatric Drugs / Issue 3/2012
Print ISSN: 1174-5878
Electronic ISSN: 1179-2019
DOI: https://doi.org/10.2165/11631360-000000000-00000

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2012

Valsartan

Olmesartan Medoxomil in Children and Adolescents with Hypertension

Management of Children with Multiple Sclerosis

Short Bowel Syndrome in Children

Prenatal Neurologic Anomalies

From Adults to Children