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Juvenile Chronic Myelogenous Leukemia (JCML)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9946/3
Note the proper terminology of this disorder is controversial; many authors, including the European Working Group on MDS in Childhood favor the term JMML; another working group suggests using the term JMML syndrome with a qualifier with or without monosomy 7 or 7q-
Other namesJuvenile myelomonocytic leukemia (JMML)
Juvenile myelomonocytic leukemia syndrome (JMML syndrome)

Clinics and Pathology

Disease JCML is a chronic myeloproliferative disorder that typically affects young children: more than 95% of cases are diagnosed before age 4
Phenotype / cell stem origin evidence exists for leukemic involvement of CD34-positive stem cells and monocyte-macrophage, erythroid, and B-lymphoid lineages in cases with cytogenetic abnormalities
Epidemiology annual incidence is estimated to be roughly 4/million; median age 1-4 yrs; sex ratio: 1.4M/1F
Clinics
  • splenomegaly, lymphadenopathy, and skin rash are common; typical peripheral blood findings include leukocytosis (usually less than 100 x 109/L), monocytosis, and thrombocytosis with variable degree of left shift; myeloblasts average about 5% of total nucleated cells; elevation of fetal hemoglobin (hbF) very common; absence of the Philadelphia chromosome in all cases
  • proposed clinical criteria from the International Juvenile Myelomonocytic Leukemia Working Group includes: 1. white blood cell count > 13 x 109/L (corrected for nucleated red blood cells)
    2. absolute monocyte count > 1 x 109/L (corrected)
    3. presence of immature myeloid precursors (myelocytes, promyelocytes, and myeloblasts) in the peripheral blood
    4. bone marrow aspirate revealing < 30% blasts
    5. no Ph chromosome on cytogenetic assessment
  • about 15% of cases are associated with neurofibromatosis type 1 ( NF-1 mutation)
  • Pathology
  • blood: leukocytosis, monocytosis, left shift in myeloid maturation, circulating mucleated red blood cells
  • bone marrow: hypercellular marrow with mildly increased M:E ratio (typically 5:1), dispersed erythroid elements, and decreased numbers of megakaryocytes; dyplasia is usually not prominent
  • Treatment intensive chemotherapy and all trans retinoic have not been shown to induce durable remissions; complete remissions have been achieved with stem cell transplantation
    Prognosis the disease is uniformly fatal when treated with conventional chemotherapy; among those who undergo bone marrow transplantations, the majority ultimately relapse, with an overall survival rate of 25%

    Cytogenetics

    Cytogenetics Morphological other than the frequent association with monosomy 7, no consistent cytogenetic abnormalities have been identified; whether the infantile monosomy 7 syndrome is distinct from JCML is controversial

    Genes involved and Proteins

    Note mechanisms of Oncogenesis:
    JCML patients show spontaneous growth of granulocyte-macrophage colony forming units (CFU-GM) from peripheral blood, which appears to be the result of hypersensitivity to GM-CSF, IL-3, or SCF; cases associated with NF-1 are likely to be the result of constitutive activation of the Ras pathway as a result of decreased GT Pase activity although there is also evidence of a GAP independent function; up to 30% of cases show mutations in K-ras and N-ras; the importance of the RAS pathway has been confirmed in mouse models with targeted disrupted of Nf-1; recently data suggest that TNFa produced by neoplastic cells may prevent expansion of hematopoietic progenitors

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

    Genes ASXL1 GAB2 SPECC1 JAK2 PDGFRB PTPN11

    Translocations implicated (Data extracted from papers in the Atlas)

    Bibliography

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    Nature genetics. 1996 ; 12 (2) : 144-148.
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    Hess JL, Zutter MM, Castleberry RP, Emanuel PD
    American journal of clinical pathology. 1996 ; 105 (2) : 238-248.
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    Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.
    Largaespada DA, Brannan CI, Jenkins NA, Copeland NG
    Nature genetics. 1996 ; 12 (2) : 137-143.
    PMID 8563750
     
    Juvenile myelomonocytic leukemia: analyses of treatment results in the EORTC Children's Leukemia Cooperative Group (CLCG).
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    Bone marrow transplantation. 1996 ; 18 (6) : 1111-1116.
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    Loss of heterozygosity of NF1 gene in juvenile chronic myelogenous leukemia with neurofibromatosis type 1.
    Kai S, Sumita H, Fujioka K, Takahashi H, Hanzawa N, Funabiki T, Ikuta K, Sasaki H
    International journal of hematology. 1998 ; 68 (1) : 53-60.
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    Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.
    Zhang YY, Vik TA, Ryder JW, Srour EF, Jacks T, Shannon K, Clapp DW
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    PMID 9607929
     
    Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS).
    Hasle H, Aricˆ¾ M, Basso G, Biondi A, Cantˆ¼ 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, Starˆ‡ J, Stollmann-Gibbels B, Testi AM, van Wering ER, Zimmermann M
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 ; 13 (3) : 376-385.
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    Juvenile myelomonocytic leukemia: what we don't know.
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    Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology. 1999 ; 21 (6) : 461-463.
    PMID 10598653
     
    Nf1 and Gmcsf interact in myeloid leukemogenesis.
    Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM
    Molecular cell. 2000 ; 5 (1) : 189-195.
    PMID 10678181
     
    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 ; 96 (6) : 2310-2313.
    PMID 10979983
     
    Myelodysplastic syndromes in children. A critical review of the clinical manifestations and management.
    Novitzky N
    American journal of hematology. 2000 ; 63 (4) : 212-222.
    PMID 10706766
     
    Alternative donor bone marrow transplantation for children with juvenile myelomonocytic leukemia.
    Bunin N, Saunders F, Leahey A, Doyle J, Calderwood S, Freedman MH.
    J Ped Hematol Oncol 1999; 21: 461-463.
    PMID 20065717
     
    Nf1 and GM-CSF interact in myeloid leukemogenesis.
    Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM.
    Molecular Cell 2000; 5: 189-195.
    PMID 20142671
     
    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; 96: 2310-2313.
    PMID 20435367
     
    Myelodysplastic syndromes in children. A critical review of the clinical manifestations and mangement.
    Novitzky N.
    Am J Hematol 2000; 63: 212-222.
    PMID 20170720
     
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    Contributor(s)

    Written12-2000Jay L. Hess

    Citation

    This paper should be referenced as such :
    Hess, JL
    Juvenile chronic myelogenous leukemia (JCML)
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):35-36.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Anomalies/JCMLID1099.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Sep 25 15:34:47 CEST 2014


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