Top

Published in:

01-09-2015 | Original Article

Pediatric myelodysplastic/myeloproliferative neoplasms and related diseases

Authors: Karthik A. Ganapathi, Kristian T. Schafernak, V. Koneti Rao, Katherine R. Calvo

Published in: Journal of Hematopathology | Issue 3/2015

Abstract

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders with myeloproliferative features, varying degrees of dysplasia and cytopenias, and increased propensity for progression to acute myeloid leukemia (AML). MDS/MPN are uncommon in the pediatric age group, and best exemplified by Juvenile myelomonocytic leukemia (JMML), a rare but aggressive leukemia of early childhood. Remarkable progress has been made in understanding the genetic basis of JMML leading to improved diagnostic criteria and better management. It is now understood that JMML is associated with somatic or germ line mutations in NF1, NRAS, KRAS, PTPN11, and CBL in greater than 90 % of cases with the common downstream mechanism being uncontrolled activation of the RAS/MAPK pathway. More recently, KRAS and NRAS mutations have also been identified in RAS-associated autoimmune leukoproliferative disorder (RALD), which shares some clinical, hematopathological, and genetic features with JMML, but has an indolent clinical course. Hematopoietic stem cell transplant (HSCT) is currently the only curative therapy for JMML, although newer therapeutic agents are currently in clinical trials. This review will focus primarily on the current clinical features, diagnostic criteria, pathologic features, and therapy of JMML and provide a brief description of RALD.

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, Lyon

Niemeyer CM (2014) RAS diseases in children. Haematologica 99(11):1653–1662. doi:10.3324/haematol.2014.114595 PubMedCentralPubMedCrossRef

Zoi K, Cross NC (2015) Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable. Int J Hematol 101(3):229–242. doi:10.1007/s12185-014-1670-3 PubMedCrossRef

Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G, Locatelli F, Mann G, Stollmann-Gibbels B, van’t Veer-Korthof ET, van Wering E, Zimmermann M (1997) Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 89(10):3534–3543PubMed

Luna-Fineman S, Shannon KM, Atwater SK, Davis J, Masterson M, Ortega J, Sanders J, Steinherz P, Weinberg V, Lange BJ (1999) Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93(2):459–466PubMed

Emanuel PD, Bates LJ, Castleberry RP, Gualtieri RJ, Zuckerman KS (1991) Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77(5):925–929PubMed

Proytcheva M (2011) Juvenile myelomonocytic leukemia. Semin Diagn Pathol 28(4):298–303PubMedCrossRef

Chang TY, Dvorak CC, Loh ML (2014) Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia. Blood 124(16):2487–2497. doi:10.1182/blood-2014-03-300319 PubMedCrossRef

Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, Shannon K (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med 336(24):1713–1720. doi:10.1056/NEJM199706123362404 PubMedCrossRef

10.

Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, Flotho C (2010) Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica 95(2):320–323PubMedCentralPubMedCrossRef

11.

Bader-Meunier B, Tchernia G, Mielot F, Fontaine JL, Thomas C, Lyonnet S, Lavergne JM, Dommergues JP (1997) Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 130(6):885–889PubMedCrossRef

12.

Side LE, Shannon KM (1997) Myeloid disorders in infants with Noonan syndrome and a resident’s “rule” recalled. J Pediatr 130(6):857–859PubMed

13.

Choong K, Freedman MH, Chitayat D, Kelly EN, Taylor G, Zipursky A (1999) Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21(6):523–527PubMedCrossRef

14.

Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70(6):1555–1563PubMedCentralPubMedCrossRef

15.

Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34(2):148–150PubMedCrossRef

16.

Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM (2004) Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103(6):2325–2331PubMedCrossRef

17.

Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG (2004) Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 10(8):849–857PubMedCrossRef

18.

Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, Morgan K, Boulton C, Shigematsu H, Keilhack H, Akashi K, Gilliland DG, Neel BG (2005) Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7(2):179–191PubMedCrossRef

19.

Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M, Loh ML (2005) The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106(6):2183–2185. doi:10.1182/blood-2005-02-0531 PubMedCentralPubMedCrossRef

20.

Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S (1994) Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83(8):2248–2254PubMed

21.

Flotho C, Valcamonica S, Mach-Pascual S, Schmahl G, Corral L, Ritterbach J, Hasle H, Arico M, Biondi A, Niemeyer CM (1999) RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13(1):32–37PubMedCrossRef

22.

Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel P-G, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42(9):794–800PubMedCentralPubMedCrossRef

23.

Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M, Kon A, Sanada M, Chiba K, Tanaka H, Makishima H, Wang X, Xu Y, Doisaki S, Hama A, Nakanishi K, Takahashi Y, Yoshida N, Maciejewski JP, Miyano S, Ogawa S, Kojima S (2013) Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45(8):937–941. doi:10.1038/ng.2698 PubMedCrossRef

24.

Sugimoto Y, Muramatsu H, Makishima H, Prince C, Jankowska AM, Yoshida N, Xu Y, Nishio N, Hama A, Yagasaki H, Takahashi Y, Kato K, Manabe A, Kojima S, Maciejewski JP (2010) Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations. Br J Haematol 150(1):83–87PubMed

25.

Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML (2009) Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 33(3):355–362. doi:10.1016/j.leukres.2008.08.022 PubMedCentralPubMedCrossRef

26.

Dvorak CC, Loh ML (2014) Juvenile myelomonocytic leukemia: molecular pathogenesis informs current approaches to therapy and hematopoietic cell transplantation. Front Pediatr 2:25. doi:10.3389/fped.2014.00025 PubMedCentralPubMedCrossRef

27.

Hasegawa D, Bugarin C, Giordan M, Bresolin S, Longoni D, Micalizzi C, Ramenghi U, Bertaina A, Basso G, Locatelli F, Biondi A, Te Kronnie G, Gaipa G (2013) Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia. Blood Cancer J 3:e160. doi:10.1038/bcj.2013.56 PubMedCentralPubMedCrossRef

28.

Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y, Hama A, Nishio N, Muramatsu H, Watanabe N, Matsumoto K, Kato K, Ueyama J, Inada H, Goto H, Yabe M, Kudo K, Mimaya J, Kikuchi A, Manabe A, Koike K, Kojima S (2009) Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res 65(3):334–340. doi:10.1203/PDR.0b013e3181961d2a PubMedCrossRef

29.

Matsuda K, Shimada A, Yoshida N, Ogawa A, Watanabe A, Yajima S, Iizuka S, Koike K, Yanai F, Kawasaki K, Yanagimachi M, Kikuchi A, Ohtsuka Y, Hidaka E, Yamauchi K, Tanaka M, Yanagisawa R, Nakazawa Y, Shiohara M, Manabe A, Kojima S, Koike K (2007) Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 109(12):5477–5480. doi:10.1182/blood-2006-09-046649 PubMedCrossRef

30.

Flotho C, Kratz CP, Bergstrasser E, Hasle H, Stary J, Trebo M, van den Heuvel-Eibrink MM, Wojcik D, Zecca M, Locatelli F, Niemeyer CM, European Working Group of Myelodysplastic Syndromes in C (2008) Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. Blood 111(2):966–967. doi:10.1182/blood-2007-09-111831 PubMedCrossRef

31.

Bresolin S, Zecca M, Flotho C, Trentin L, Zangrando A, Sainati L, Stary J, de Moerloose B, Hasle H, Niemeyer CM, Te Kronnie G, Locatelli F, Basso G (2010) Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol 28(11):1919–1927PubMedCrossRef

32.

Locatelli F, Crotta A, Ruggeri A, Eapen M, Wagner JE, Macmillan ML, Zecca M, Kurtzberg J, Bonfim C, Vora A, Diaz de Heredia C, Teague L, Stein J, O’Brien TA, Bittencourt H, Madureira A, Strahm B, Peters C, Niemeyer C, Gluckman E, Rocha V (2013) Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 122(12):2135–2141. doi:10.1182/blood-2013-03-491589 PubMedCentralPubMedCrossRef

33.

Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G, Head DR (2003) A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17(2):277–282. doi:10.1038/sj.leu.2402765 PubMedCrossRef

34.

DiNardo CD, Daver N, Jain N, Pemmaraju N, Bueso-Ramos C, Yin CC, Pierce S, Jabbour E, Cortes JE, Kantarjian HM, Garcia-Manero G, Verstovsek S (2014) Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia 28(4):958–961. doi:10.1038/leu.2014.8 PubMedCentralPubMedCrossRef

35.

Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A 104(21):8953–8958. doi:10.1073/pnas.0702975104 PubMedCentralPubMedCrossRef

36.

Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, Muramatsu H, Doisaki S, Nagasawa M, Morio T, Kasahara Y, Koike K, Kojima S, Takao A, Mizutani S (2011) Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 117(10):2887–2890. doi:10.1182/blood-2010-08-301515 PubMedCrossRef

37.

Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, Rieux-Laucat F, Siegel RM, Su HC, Teachey DT, Rao VK (2010) Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 116(14):e35–e40. doi:10.1182/blood-2010-04-280347 PubMedCentralPubMedCrossRef

38.

Calvo KR, Price S, Braylan RC, Oliveira JB, Lenardo M, Fleisher TA, Rao VK (2015) JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities. Blood 125(18):2753–2758. doi:10.1182/blood-2014-11-567917 PubMedCrossRef

39.

Lanzarotti N, Bruneau J, Trinquand A, Stolzenberg MC, Neven B, Fregeac J, Levy E, Jeremiah N, Suarez F, Mahlaoui N, Fischer A, Magerus-Chatinet A, Cave H, Rieux-Laucat F (2014) RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia. Blood 123(12):1960–1963. doi:10.1182/blood-2014-01-548958 PubMedCrossRef

40.

Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M, Beer LA, Dowdell KC, Pittaluga S, Raffeld M, Rao VK, Oliveira JB (2011) Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood 117(10):2883–2886. doi:10.1182/blood-2010-07-295501 PubMedCentralPubMedCrossRef

41.

Takagi M, Piao J, Lin L, Kawaguchi H, Imai C, Ogawa A, Watanabe A, Akiyama K, Kobayashi C, Mori M, Ko K, Sugimoto M, Mizutani S (2013) Autoimmunity and persistent RAS-mutated clones long after the spontaneous regression of JMML. Leukemia 27(9):1926–1928. doi:10.1038/leu.2013.82 PubMedCrossRef

Title: Pediatric myelodysplastic/myeloproliferative neoplasms and related diseases
Authors: Karthik A. Ganapathi
Kristian T. Schafernak
V. Koneti Rao
Katherine R. Calvo
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: Journal of Hematopathology / Issue 3/2015
Print ISSN: 1868-9256
Electronic ISSN: 1865-5785
DOI: https://doi.org/10.1007/s12308-015-0250-7

At a glance: The STEP trials

Springer Medicine

Pediatric myelodysplastic/myeloproliferative neoplasms and related diseases

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2015

Myeloid proliferations associated with Down syndrome

Molecular characterization and testing in acute myeloid leukemia

Myeloproliferative neoplasms in children

Pediatric myelodysplastic syndromes

Flow cytometry in the diagnosis and monitoring of acute leukemia in children

Paediatric hematopathology: something real special