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Juvenile myelomonocytic leukemia (JMML)

Written2019-08Karen M. Chisholm
Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA;
This article is an update of :
2000-12Jay L. Hess
Department of Pathology, The University of Michigan, M5240 Medical Science I, 1301 Catherine Avenue, Ann Arbor, MI 48109-0602, USA

Abstract Review on juvenile myelomonocytic leukemia, with data on clinics, pathology, and involved genes.

Keywords Juvenile myelomonocytic Leukemia, Myelodysplastic syndrome, Myeloproliferative disorder, Pediatric

(Note : for Links provided by Atlas : click)


ICD-Morpho 9946/3 Juvenile myelomonocytic leukaemia
Atlas_Id 1099
Note This current topic of JMML does not include discussion on Ras-associated autoimmune leukoproliferative disorder (RALD), which is a nonmalignant disorder with myelomonocytic hyperplasia and somatic mutations in KRAS or NRAS, often showing clinical overlap with JMML (Calvo et al., 2015)
Other namesJuvenile chronic myelogenous leukemia (JCML);
Juvenile chronic myelomonocytic leukemia

Clinics and Pathology

Disease JMML is a chronic myeloproliferative disorder that typically affects young children: more than 95% of cases are diagnosed before age 4
Phenotype / cell stem origin JMML arises from pluripotent hematopoietic stem cells (Cooper et al., 2000). Clonal proliferations of myeloid, monocyte-macrophages, erythroid, and sometimes lymphoid progenitor cells are seen.
Epidemiology The annual incidence of JMML is estimated to be roughly 0.67/million (Passmore et al, 2003). The median age is 1.1-1.8 years with a male to female ratio of 2-3:1. (Hasle et al., 1999; Niemeyer et al., 1997; Passmore et al., 2003). Those with neurofibromatosis type 1 (NF-1) have a 200-fold increased risk of JMML (Stiller et al., 1994)
  • Children with JMML commonly have splenomegaly, lymphadenopathy, and skin rashes (Hess et al., 1996). Involvement of the liver, lung, and GI tract can also occur.
  • The diagnostic criteria for JMML are:
    Clinical and hematologic features (all 4 required)  
  • Peripheral blood monocyte count ≥1 x 109/L
  • Peripheral blood and bone marrow blast percentages <20%
  • Splenomegaly
  • No Philadelphia (Ph) chromosome or BCR-ABL1 fusion

    Genetic criteria (1 finding is sufficient)

  • Somatic mutation in PTPN11 , KRAS, or NRAS
  • Clinical diagnosis of neurofibromastosis type 1 or NF1 mutation
  • Germline CBL mutation and loss of heterozygosity of CBL

    Other criteria*

  • Monosomy 7 or any other chromosomal abnormality


      ≥  2 of the following:
  • Increased hemoglobin F (HbF) for age
  • Myeloid or erythroid precursors on peripheral blood smear
  • Granulocyte-macrophages colony-stimulating factor (GM-CSF) hypersensitivity in colony assay
  • Hyperphosphorylation of STAT5

  • * (those not meeting genetic criteria but having clinical and hematologic criteria must also have).
    (Locatelli and Neimeyer, 2015; Baumann, et al., 2017)
  • Cytology Typical peripheral blood findings include leukocytosis (usually less than 100 x 109/L) with variable degree of left shift, monocytosis, and thrombocytopenia. Nucleated red blood cells are often identified in the peripheral blood. Myeloblasts average about 1-5% of total nucleated cells, and by definition, blasts account for <20% of cells. (Hess et al., 1996; Niemeyer et al., 1997)
    Pathology Bone marrow findings are not specific. The marrow is usually hypercellular with a mildly increased M:E ratio (typically 3-5:1), dispersed erythroid elements, and decreased numbers of megakaryocytes. Dysplasia is usually not prominent. Blasts are required to be less than 20%; monocytes are less prominent in the marrow than in the peripheral blood, and are usually enumerated at 5-10% (Hess et al., 1996; Niemeyer et al., 1997).
    A 21 month old boy presented with peripheral monocytosis, increased fetal hemoglobin. His bone marrow aspirate showed <20% blasts. Cytogenetics identified monosomy 7, and genetic testing identified a PTPN11 mutation. This bone marrow core biopsy demonstrates a hypercellular marrow with decreased megakaryocytes.
    Other features Aberrant flow immunophenotype antigens can be seen in monocytes, neutrophils, and blasts in JMML. Monocytes can show decreased expression of CD4 and heterogeneous CD33. Maturing neutrophils may show decreased expression of CD10, CD64, CD13, and/or CD15. Myeloid blasts can express aberrant CD7. B cell precursors (hematogones) are often decreased (Maioli et al. 2016).
    Treatment Curative therapy involves an allogeneic hematopoietic stem cell transplant (HSCT). Locatelli and Neimeyer (2015) recommend swift HSCT for those with germline NF1 mutations, somatic PTPN11 mutations, somatic KRAS mutations, and most children with somatic NRAS mutations. Most children with germline CBL mutations demonstrate spontaneous regression, though if there is disease progression, a HSCT should be considered. In children with Noonan syndrome (germline mutations of PTPN11, KRAS, and/or NRAS), the disease may be transient, and hence one can consider a 'watch and wait' scenario, with mild cytoreductive therapy for symptoms, usually 6-mercaptopruine.
    In the rare patients with tyrosine kinase fusions, ALK/ROS1 inhibitors, such as crizotinib, may be beneficial (Murakami et al., 2018).
    Evolution As stated above, those with Noonan syndrome with germline mutations in PTPN11, KRAS, and/or NRAS as well as those with germline CBL mutations have disease that may spontaneously regress without therapy (Locatelli and Neimeyer, 2015). However, in other cases, in those who did not receive an allogeneic hematopoietic stem cell transplant (HSCT), the median survival after diagnosis is <12 months (Niemeyer et al., 1997). In those who receive HSCT, the 5-year overall survival rate is 64%, with an event free survival of 52% (Locatelli et a., 2005). The 5-year cumulative incidence of relapse is 35%, while the 5-year cumulative incidence of transplantation-related mortality is 13% (Locatelli et al., 2005)
    Prognosis High risk features include older age (>1.4-4 years), PTPN11 mutation, monosomy 7, HbF >40%, low platelets (<33K/uL), and >20% bone marrow blasts (Dvorak and Loh, 2014; Locatelli et al., 2005; Niemeyer et al., 1997; Novitzky et al., 2000; Passmore et al., 2003). In genetic studies, patients with <2 somatic alterations have improved outcomes compared to those with ≥2 alterations (Stiegliz et al., 2015). DNA methylation studies have also been done, showing three clusters of methylation in JMML; those with the highest levels of methylation have been found to have poorer clinical outcomes (Lipka et al., 2017; Stieglitz et al., 2017).


    Approximately 85-90% of children with JMML have identified mutations, either germline and/or somatic. Somatic, gain-of-function mutations occur in PTPN11, KRAS, and NRAS, in 35-38%, 18%, and 14% of cases respectively. NF1 germline mutations with acquired loss of the normal allele are seen in 5-15% of patients, and CBL germline mutations with acquired loss of the normal allele and duplication of the mutant allele (acquired uniparental disomy) are seen in 9-18% of patients. (Chan et al., 2009; Niemeyer and Flotho, 2019). Rare cases without any of the above mutations have been found to harbor RRAS or RRAS2 somatic mutations (Stieglitz et al., 2015).
    Secondary mutations in SETBP1, JAK3, ASXL1, and SH2B3 are also identified and are often subclonal. Additional mutations in the RAS pathway genes are also sometimes detected, coined 'Ras double mutants' (Caye et al., 2015; Stieglitz et al., 2015).
    A recent study reported receptor tyrosine kinase fusions ( DCTN1 /ALK, RANBP2 /ALK, and TBL1XR1 / ROS1) in patients without identified RAS pathway mutations (Murakami et al., 2018).


    Note Normal karyotypes are present in most cases of JMML (~68%). Another 16-25% of cases have monosomy 7 or deletion 7q (Aricò et al, 1997; Niemeyer et al., 1997).

    Genes involved and Proteins

    Gene NameCBL
    Location 11q23.3
    Note There is a high rate of spontaneous resolution of disease without stem cell transplant in those with homozygous mutations including a germline mutation (Chang et al., 2014).
    Dna / Rna 16 exons.
    Protein This oncogene encodes a RING finger E3 ubiquitin ligase which marks activated receptor and nonreceptor tyrosine kinases and other proteins for degradation by ubiquitination. Homozygous mutations lead to continuous activation of RAS. (Chang et al., 2014).
    Germinal mutations Germline heterozygous mutations (autosomal dominant) lead to a Noonan syndrome-like disorder. The most common mutation is c.1111T>C (Y371H); other common mutations are missense mutations in exons 8 and 9 or in introns 7 or 8 (Loh et al., 2009).
    Somatic mutations Loss of wild-type allele with duplication of mutant allele.
    Gene NameKRAS
    Location 12p12.1
    Note Somatic mutations also occur in RALD (Ras-associated lymphoproliferative disease).
    Dna / Rna 6 exons.
    Protein A Ras oncogene which encodes a member of the small GTPase superfamily. Mutations lead to activation.
    Germinal mutations Germline heterozygous mutations (autosomal dominant) lead to Noonan syndrome.
    Somatic mutations Somatic mutations are usually point mutations at codons G12, G13, and Q61 (exons 2 and 3) leading to amino acid substitutions (Chan et al., 2009; Chang et al., 2014).
    Gene NameNF1 (neurofibromin 1)
    Location 17q11.2
    Dna / Rna 57-58 exons (depending on transcript variant).
    Protein GTPase activating protein for Ras. Normally acts as tumor suppressor by inhibiting Ras signaling
    Germinal mutations Germline mutations cause neurofibromatosis type 1 (NF1) characterized by café-au-lait spots, Lisch nodules, neurofibromas, optic pathway gliomas.
    Somatic mutations Somatic mutations are usually deletions leading to loss of heterozygosity with duplication of the mutated germline allele.
    Gene NameNRAS
    Location 1p13.2
    Note Somatic mutations also occur in RALD (Ras-associated lymphoproliferative disease).
    Dna / Rna 7 exons.
    Protein A Ras oncogene which encodes a membrane protein with intrinsic GTPase activity that shuttles between the Golgi apparatus and the plasma membrane.
    Germinal mutations Germline heterozygous mutations (autosomal dominant) lead to Noonan syndrome.
    Somatic mutations Somatic mutations are usually point mutations at codons G12, G13, and Q61 (exons 2 and 3) leading to amino acid substitutions (Chan et al., 2009; Chang et al., 2014).
    Gene NamePTPN11
    Location 12q24.13
    Dna / Rna 16 exons
    Protein A member of the protein tyrosine phosphatase family which relays signals from activated GM-CSF receptor complexes, regulating proliferation, differentiation, and migration.
    Germinal mutations Germline mutations (autosomal dominant) lead to Noonan syndrome, usually within exons 3, 4, and 13.
    Somatic mutations Somatic mutations usually involve exons 3, 4, and 13, with most common mutations being: c.226G>A (E76K), c.214G>A, c.227A>G, c.1508G>C. (Chan et al., 2009; Chang et al., 2014).


    Juvenile myelomonocytic leukemia
    Aricò M, Biondi A, Pui CH
    Blood 1997 Jul 15;90(2):479-88
    PMID 9226148
    Juvenile myelomonocytic leukaemia
    Baumann I, Bennett JM, Neimeyer CM, Thiele J.
    WHO Classification of Tumours of Haematopoietic and Lymphoid tissues. Editors: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. International Agency for Research on Cancer, Lyon, 2017. Pgs 89-92
    Biological assay of fungicides against yeasts in vitro using a coulter counter
    Brotherton J
    Mykosen 1976 Oct;19(10):361-72
    PMID 794710
    JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities
    Calvo KR, Price S, Braylan RC, Oliveira JB, Lenardo M, Fleisher TA, Rao VK
    Blood 2015 Apr 30;125(18):2753-8
    PMID 25691160
    Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network
    Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, Lainey E, Nouri K, Nakhaei-Rad S, Dvorsky R, Lachenaud J, Pereira S, Vivent J, Verger E, Vidaud D, Galambrun C, Picard C, Petit A, Contet A, Poirée M, Sirvent N, Méchinaud F, Adjaoud D, Paillard C, Nelken B, Reguerre Y, Bertrand Y, Häussinger D, Dalle JH, Ahmadian MR, Baruchel A, Chomienne C, Cavé H
    Nat Genet 2015 Nov;47(11):1334-40
    PMID 26457648
    Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium
    Chan RJ, Cooper T, Kratz CP, Weiss B, Loh ML
    Leuk Res 2009 Mar;33(3):355-62
    PMID 18954903
    Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia
    Chang TY, Dvorak CC, Loh ML
    Blood 2014 Oct 16;124(16):2487-97
    PMID 25163700
    Evidence that juvenile myelomonocytic leukemia can arise from a pluripotential stem cell
    Cooper LJ, Shannon KM, Loken MR, Weaver M, Stephens K, Sievers EL
    Blood 2000 Sep 15;96(6):2310-3
    PMID 10979983
    Juvenile myelomonocytic leukemia: molecular pathogenesis informs current approaches to therapy and hematopoietic cell transplantation
    Dvorak CC, Loh ML
    Front Pediatr 2014 Mar 28;2:25
    PMID 24734223
    Hanke J, Indulski JA
    Med Pr 1988;39(3):186-92
    PMID 3067044
    Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7
    Hasle H, Aricò M, Basso G, Biondi A, Cant Rajnoldi A, Creutzig U, Fenu S, Fonatsch C, Haas OA, Harbott J, Kardos G, Kerndrup G, Mann G, Niemeyer CM, Ptoszkova H, Ritter J, Slater R, Starý J, Stollmann-Gibbels B, Testi AM, van Wering ER, Zimmermann M
    European Working Group on MDS in Childhood (EWOG-MDS) Leukemia
    PMID 10086728
    Juvenile chronic myelogenous leukemia
    Hess JL, Zutter MM, Castleberry RP, Emanuel PD
    Am J Clin Pathol 1996 Feb;105(2):238-48
    PMID 8607451
    RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia
    Lipka DB, Witte T, Toth R, Yang J, Wiesenfarth M, Nöllke P, Fischer A, Brocks D, Gu Z, Park J, Strahm B, Wlodarski M, Yoshimi A, Claus R, Lübbert M, Busch H, Boerries M, Hartmann M, Schönung M, Kilik U, Langstein J, Wierzbinska JA, Pabst C, Garg S, Catalá A, De Moerloose B, Dworzak M, Hasle H, Locatelli F, Masetti R, Schmugge M, Smith O, Stary J, Ussowicz M, van den Heuvel-Eibrink MM, Assenov Y, Schlesner M, Niemeyer C, Flotho C, Plass C
    Nat Commun 2017 Dec 19;8(1):2126
    PMID 29259247
    How I treat juvenile myelomonocytic leukemia
    Locatelli F, Niemeyer CM
    Blood 2015 Feb 12;125(7):1083-90
    PMID 25564399
    Mutations in CBL occur frequently in juvenile myelomonocytic leukemia
    Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM
    Blood 2009 Aug 27;114(9):1859-63
    PMID 19571318
    Flow cytometry as a diagnostic support tool in juvenile myelomonocytic leukemia
    Maioli MC, Fernandez Tde S, Campos MM, Diamond HR, Veranio-Silva GA, de Souza AM, da Costa ES, Ornellas MH, Thiago LS
    Leuk Lymphoma 2016;57(1):233-6
    PMID 25956043
    Integrated molecular profiling of juvenile myelomonocytic leukemia
    Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H
    Blood 2018 Apr 5;131(14):1576-1586
    PMID 29437595
    Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases
    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
    European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood
    PMID 9160658
    Myelodysplastic syndromes in children
    Novitzky N
    A critical review of the clinical manifestations and management Am J Hematol
    PMID 10706766
    Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival
    Passmore SJ, Chessells JM, Kempski H, Hann IM, Brownbill PA, Stiller CA
    Br J Haematol 2003 Jun;121(5):758-67
    PMID 12780790
    Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia
    Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Akutagawa J, Lipka DB, Plass C, Flotho C, Chehab FF, Braun BS, Costello JF, Loh ML
    Nat Commun 2017 Dec 19;8(1):2127
    PMID 29259179


    This paper should be referenced as such :
    Karen M Chisholm
    Juvenile myelomonocytic leukemia (JMML)
    Atlas Genet Cytogenet Oncol Haematol. 2020;24(4):180-184.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Hess, JL. Juvenile chronic myelogenous leukemia (JCML). Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):35-36.

    Other genes implicated (Data extracted from papers in the Atlas) [ 7 ]


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