Juvenile Myelomonocytic Leukemia: Bench to Bedside and Back Again
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.
The World Health Organization has recently classified JMML as one of four diseases classified in the
mixed myelodysplastic/myeloproliferative category.  JMML is a clonal disease process of
pluripotent stem cell origin.
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.  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.  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.
occasional cases of other leukemias/MPDs demonstrate spontaneous colony growth,  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.
Many of the JMML patients with clinical
neurofibromatosis type 1 have been shown to have loss of heterozygosity for the NF1 gene.  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.  Hematopoietic cells harvested from mice in whom the
Nf1 gene has been homozygously deleted demonstrate the same selective
hypersensitivity to GM-CSF,
and these cells are critically dependent upon gm-csf for
survival.  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.  PTPN11 gene mutations are identified in ~35%
of JMML patients, regardless of whether the patient has Noonan syndrome or not.
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.  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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