Key points

Introduction

Juvenile myelomonocytic leukemia (JMML) is a rare myeloid malignancy that occurs in young children. Similar to other myeloid neoplasms, such as chronic myeloid leukemia (CML) and some cases of acute myeloid leukemia (AML), or to premalignant disorders, such as myelodysplastic syndrome (MDS), JMML is a disorder of myeloid progenitors, or stem cells.

Because of its rarity and because of its varied clinical presentations, JMML is often difficult for general pediatricians, pediatric oncologists, and even for hematopathologists to diagnose. Clinically, a child with JMML may exhibit symptoms that suggest a common viral syndrome. Blood counts and hematologic features may mimic AML. Over the last decade, however, significant progress has been made toward understanding the unique molecular mechanisms and features that render JMML distinct from similar conditions.

Introduction

Juvenile myelomonocytic leukemia (JMML) is a rare myeloid malignancy that occurs in young children. Similar to other myeloid neoplasms, such as chronic myeloid leukemia (CML) and some cases of acute myeloid leukemia (AML), or to premalignant disorders, such as myelodysplastic syndrome (MDS), JMML is a disorder of myeloid progenitors, or stem cells.

Because of its rarity and because of its varied clinical presentations, JMML is often difficult for general pediatricians, pediatric oncologists, and even for hematopathologists to diagnose. Clinically, a child with JMML may exhibit symptoms that suggest a common viral syndrome. Blood counts and hematologic features may mimic AML. Over the last decade, however, significant progress has been made toward understanding the unique molecular mechanisms and features that render JMML distinct from similar conditions.

Epidemiology, nomenclature, clinical presentation, and differential diagnosis

Clinical Presentation

JMML most often occurs in children younger than 2 years old, and almost always before puberty. Children affected with JMML usually present with fever, respiratory symptoms, skin rash, and hepatosplenomegaly. In children with high burden of disease, hepatosplenomegaly may be significant and respiratory symptoms may be severe. JMML can be associated with NF-1 and in these patients the classic café-au-lait spots may take on a slightly unusual form. Laboratory tests are significant for elevated white blood cell counts with an atypical monocytosis and associated thrombocytopenia. Immature granulocytic precursors and nucleated red cells are evident in most cases, and the peripheral blood blast cell percentage averages 2% and rarely exceeds 20%. The diagnosis of JMML is supported when, in the setting of the previously mentioned symptoms, a patient has an absolute monocyte count exceeding 1 × 10 ⁹ /L in the peripheral blood. However, other possible causes, such as CML, must be excluded.

Bone marrow aspirate is not always required to make the diagnosis of JMML; however, it can be suggestive of the diagnosis in the right clinical setting. Unlike in AML, the bone marrow in patients with JMML demonstrates no blockage of differentiation of myeloid elements ( Fig. 1 ). Rather, as is seen in CML, the bone marrow in JMML exhibits myeloid hyperplasia with granulocytic cells at varying stages of maturation. The marrow blast count may be slightly elevated but in classic JMML it does not reach the counts seen in AML. Rare cases of JMML have been described with a predominance of erythroid precursors in the marrow and mimicking acute erythroblastic leukemia. Megakaryocytes are reduced in number and this is mirrored by evidence of thrombocytopenia in the peripheral blood. Of interest, monocytosis seen in the bone marrow is less pronounced than it is in the peripheral blood.

Schematic diagram of ( A ) normal hematopoietic differentiation; ( B ) accumulation of undifferentiated myeloblasts representing acute myeloid leukemia; and ( C ) increased production of monocytic cells along the full spectrum of differentiation, including blast forms, promonocytes, monocytes, and macrophages, as observed in juvenile myelomonocytic leukemia. CMP, common myeloid progenitor; GMP, granulocyte monocyte progenitor; HSC, hematopoietic stem cell.

( From Chan RJ, Cooper T, Kratz CP, et al. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 2009;33(3):356; with permission.)

Cellular basis of juvenile myelomonocytic leukemia

JMML is considered a clonal disease originating in pluripotent stem cells of the hematopoietic system. The disease is characterized by clonal proliferation of myeloid, erythroid, and occasionally lymphoid progenitor cells.

Using clonality assays based on the differential DNA methylation of X chromosomes and on the detection of a transcriptional polymorphism of the active X chromosome, Busque and colleagues demonstrated the monoclonal origin of JMML (CD34 ⁺ /CD38) cells granulocytes, monocytes, erythroid progenitors, and megakaryocytes. The pathogenesis of JMML involves disruption of signal transduction through the RAS pathway, with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony–stimulating factor (GM-CSF).

Molecular aberrations in juvenile myelomonocytic leukemia

In vitro hypersensitivity to GM-CSF is one of the criteria for the diagnosis of JMML. However, specific molecular aberrations in GM-CSF receptors have never been clearly implicated in the pathogenesis of the disease. RAS proteins are signaling molecules that regulate cellular proliferation and differentiation by switching between an active guanosine triphosphate (GTP)–bound RAS and inactive guanosine diphosphate RAS form. Proteins encoded by the genes of the RAS family play a role in the transduction of extracellular signals to the nucleus and control proliferation and differentiation of many cell types ( Fig. 2 ). GM-CSF hypersensitivity results from continuous activation of the GM-CSF receptor–RAS-RAF-MEK-ERK signal transduction pathway. The active GTP RAS activates the RAF kinase, resulting in a downstream proliferative effect (see Fig. 2 ). In JMML, somatic mutations in this pathway are frequent and result in continuous activation and cell proliferation.

Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neurocardio-facio-cutaneous congenital disorders and JMML. CFC, cardia-facio-cutaneous; NL/MGCL, Noonan-like/multiple giant cell lesion.

( From Chan RJ, Cooper T, Kratz CP, et al. Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 2009;33(3):357; with permission.)

Mutations in RAS genes are found in 20% to 30% of all human malignancies. The RAS subfamily includes three members: HRAS , KRAS , and NRAS . In one study, 25% of patients with JMML were found to have a somatic NRAS or KRAS point mutation. In one-quarter of all JMML cases, activating point mutations are found in codon 12, 13, and 61 of NRAS and KRAS resulting in a continuous activation of the RAS pathway. Somatic mutations in HRAS have not been associated with JMML.

Genetic syndromes and juvenile myelomonocytic leukemia

NF-1 and NS have been instrumental in elucidating key components of the molecular pathogenesis of JMML. These genetic syndromes have germline aberrations of the RAS pathway and analysis of their pathophysiology has allowed for improved understanding of JMML pathogenesis and has enabled molecular diagnosis in 85% to 90% of cases.

In 1978 Bader and Miller noted that children affected by NF-1 were particularly prone to developing a CML or AML in the first decade of life. The NF-1 gene acts as a tumor suppressor gene and encodes neurofibromin protein. Absence of normal neurofibromin results in a relative increase in Ras-GTP and elevated levels of Ras-GTP may lead to myeloproliferative neoplasm.

Approximately 50% of children with NS have a missense germline mutation in PTPN11 gene at chromosome 12q24. Approximately 35% of patients with JMML have somatic PTPN11 mutations. In JMML, gain-of-function PTPN11 mutations affect SHP2 protein, which leads to constitutive activation of RAS pathways.

A comparison of the PTPN11 mutations in de novo and syndromic JMML (NS) reveals that many of the same codons in exons 3, 4, and 13 are affected. The precise codon substitutions, however, are distinct. The most common PTPN11 mutation in de novo JMML is the c. 226G>A, which results in E76K, an alteration that has never been documented as a germline lesion in NS. This difference in spectrum and distribution of PTPN11 mutations between de novo JMML and NS may be partly responsible for the different clinical course of myeloproliferation observed in these two groups of patients.

Casitas B-cell lymphoma mutation

Mutations in CBL were recently described in 17% of patients with JMML who were negative for NF-1, PTPN11, and RAS mutations. Mutations in c-CBL have been shown to result in continuous activation of RAS. The clinical course of JMML with associated c-CBL mutation is of particular interest. In patients with JMML and homozygous CBL mutations, high rates of spontaneous disease resolution have been reported. These patients, however, are at increased risk for the development of vasculopathies in the second decade of life unless they undergo AlloHCT. The most frequently observed vasculopathies are optic atrophy, hypertension, cardiomyopathy, and arteritis.