Juvenile myelomonocytic leukemia (JMML)

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of early childhood that originates from the multipotent hematopoietic stem and progenitor cell (HSPC) compartment. JMML is characterized by overproduction of mature and immature myeloid cells. Without adequate treatment, survival for most children is less than one year. While few cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients. Yet, even with HSCT the 5-year event-free survival still reaches only about 50%.

Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by somatic mutations in KRAS, NRAS, or PTPN11, by biallelic inactivation of NF1 or by biallelic mutations of the CBL gene. In about 90% of all JMML patients, one of these mutations can be detected in the leukemic cells. Recently, less frequent recurrent mutations in JAK3, RAC and RRAS have been identified. These new mutations also result in activation of intracellular signaling pathways including RAS and JAK/STAT signaling. RAS pathway mutations generally occur in a mutually exclusive manner in JMML and co-occurrence has only been described in some cases. Together, the emerging picture of genetic alterations suggests underlying signaling defects involving the RAS pathway in almost all cases of JMML.

So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. Overall, JMML patients with somatic NRAS mutations have a rather favorable disease outcome, whereas patients with somatic PTPN11 mutations appear to represent cases with aggressive biology and are associated with a high risk of relapse after HSCT. However, the affected RAS-pathway gene alone does not fully explain clinical outcome. Evidence from the literature suggested that oncogenic RAS-signaling is able to modify epigenetic patterns.

Using integrative analysis of genome-wide DNA methylation profiles with mutational patterns, copy-number changes and gene-expression in primary JMML samples, we have recently identified three JMML subgroups with unique molecular and clinical characteristics (Figure 3; Lipka et al, Nature Communications 2017; Stieglitz et al., Nature Communications 2017).

Our data indicates that the molecular JMML subgroups might guide clinicians in prospectively identifying those patients who need no or mild cytoreductive treatment only as compared to those patients who have a clear indication for allogeneic stem cell transplantation or those who will qualify for experimental therapies based on their high a priori risk for relapse after transplantation.

The two major goals of our ongoing research are:

• To implement molecular diagnostics into the clinical workup for every JMML patient to perform an up-front risk assessment and to be able to tailor treatment strategies according to assigned risk strata.
• To study the cause and the functional effects of epigenetic dysregulation in JMML using transgenic mouse models and xenotransplantation of primary human JMML cells.