—  SOCIETY FOR HEMATOPATHOLOGY   —

Juvenile Myelomonocytic Leukemia: Bench to Bedside and Back Again


Peter Emanuel
Comprehensive Cancer Center
University of Alabama, Birmingham, AL


Juvenile myelomonocytic leukemia (JMML) is a disorder of infancy and early childhood that carries a very poor prognosis, and in the past usually resulted in death within a year of diagnosis. [1, 2, 3, 4, 5, 6] The World Health Organization has recently classified JMML as one of four diseases classified in the mixed myelodysplastic/myeloproliferative category. [7] JMML is a clonal disease process of pluripotent stem cell origin. [8, 9] A number of other names have been ascribed to this disorder in the past including: juvenile chronic myelogneous leukemia (JCML), juvenile chronic granulocytic leukemia, chronic and subacute myelomonocytic leukemia, chronic myelomonocytic leukemia of childhood, infantile monosomy 7, and monosomy 7 syndrome. However, the name most commonly accepted in the past, JCML, did not fit well with the disease as it is clearly not a chronic disorder nor does it involve exclusive proliferation of the myeloid compartment. Further, by definition, JMML patients never exhibit the Philadelphia chromosome by karyotype analysis, nor the BCR-ABL fusion transcript by molecular analysis. JMML patients typically have marked hepatosplenomegaly, monocytosis, anemia, and thrombocytopenia. Patients often have elevated levels of fetal hemoglobin, even when corrected for age. The clinical course is frequently complicated by infiltration of various non-hematopoietic tissues (skin, lungs, intestines) with leukemic monocytic cells. Many patients succumb to JMML as a result of bleeding, infection, or organ failure due to this monocytic infiltration. [4] Only rarely (<20%) do patients demonstrate transformation to an acute leukemia-type of blast crisis. There is no evidence of maturational arrest and morphologically the abundant monocytic forms and other myeloid cell forms can either be normal in appearance or show mild-moderate dysplastic features. There are no consistently recurring chromosomal translocations in JMML, other than a loose association with monosomy 7 and other chromosome 7 abnormalities.

JMML does have a known association with two heritable genetic disorders, neurofibromatosis type 1 and Noonan syndrome. The association with these genetic disorders has provided clues to JMML pathogenesis, as elucidated below. JMML mononuclear cells have long been known to demonstrate a profound ability to proliferate in in vitro assays at very low cell densities and without exogenous growth factors. [2] This so-called "spontaneous" proliferation of granulocyte-macrophage colony forming units (CFU-GM), characteristically producing a predominance of monocytic colonies, is a consistent finding in JMML. [10, 11] However, because occasional cases of other leukemias/MPDs demonstrate spontaneous colony growth, [12] this in vitro feature lacks sufficient sensitivity and specificity to be considered a diagnostic marker for JMML. This spontaneous CFU-GM colony growth in JMML has been linked to an acquired, selective 10-fold hypersensitivity of JMML myeloid progenitor cells to GM-CSF. This in vitro selective GM-CSF hypersensitivity appears to be at present the closest diagnostic assay for JMML. While the GM-CSF receptor on JMML cells appears to be normal, GM-CSF hypersensitivity has been causally linked to hyperactivation of the Ras signaling pathway. Activating point mutations in the NRAS or KRAS genes have been demonstrated in ~20% of JMML patients. [13, 14] Many of the JMML patients with clinical neurofibromatosis type 1 have been shown to have loss of heterozygosity for the NF1 gene. [15] NF1 encodes for neurofibromin which negatively regulates Ras, and thus, NF1 functions as a tumor suppressor gene in JMML. Up to ~25% of JMML patients harbor inactivating NF1 mutations. [16] Hematopoietic cells harvested from mice in whom the Nf1 gene has been homozygously deleted demonstrate the same selective hypersensitivity to GM-CSF, [17, 18] and these cells are critically dependent upon gm-csf for survival. [19] Finally, the causative gene for Noonan syndrome, PTPN11, encodes for the phosphatase, SHP-2, which is also linked to GM-CSF signal transduction through its associations with Grb2 and Shc. Mutations in the N-SH2 domain of PTPN11 can activate the phosphatase domain which can, in turn, activate the Ras signaling pathway similar to RAS or NF1 mutations. [20] PTPN11 gene mutations are identified in ~35% of JMML patients, regardless of whether the patient has Noonan syndrome or not. [21, 22] RAS, NF1, and PTPN11 mutations all appear to be mutually exclusive in JMML patients, at least suggesting that each is solely sufficient for pathogenesis. Taken together, these three gene mutations account for up to 75% of the cases of JMML.

Clinically, JMML patients respond poorly to either low-dose or high-dose, induction type chemotherapy. Allogeneic stem cell transplantation is the only regimen proven to induce long-term remissions, but is fraught with a high, early relapse rate and a long-term survival rate of only 50%, even with today's newest transplantation approaches. Retinoic acid can produce disease stabilization in 40-50% of patients, but does not induce complete remissions as are found in acute promyelocytic leukemia. [23] Current treatment protocol strategies being attempted through the Children's Oncology Group in North America are a multi-modality regimen combining retinoids, chemotherapy, splenectomy, and stem cell transplantation in a phase III trial. Built into the trial is an up-front phase II window trial in which molecularly-targeted, mechanism-based novel therapeutics are being tested. Linked to the trial is the North American JMML Project, which is building a database as well as a cell/tissue bank for future research investigations.

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