Infant Leukemia

The vast majority of leukemia found in infants is associated with translocations involving the MLL gene (also called KMT2A). These translocations generate a novel fusion (chimeric) protein comprised of the amino terminus of MLL fused to a carboxy terminus derived from a partner gene. The MLL-fusion protein acts as a transcription factor and upregulates the expression of specific genes. We are studying the role of these genes that are regulated by the MLL-fusion protein with the goal of identifying biologic pathways that could targeted by novel therapies. Using inducible knockout mice combined with MLL-AF9 knockin mice, we recently reported on the role Meis1 in MLL-fusion leukemias. We found that Meis1 is required for the propagation of established leukemia. Further, we found that Meis1 regulates the expression of another gene – HLF, and the Meis1-HLF axis in turn was important for regulating oxidative stress. We are currently investigating the mechanisms by which HLF regulates oxidative stress and self-renewal in these leukemias. Additionally, we continue to explore the roles of other genes that are regulated by the MLL-fusion protein.

MLL-fusion proteins (eg. MLL-AF9), up-regulate the expression of genes such as MEIS1, PBX and HOX. Previous studies showed the presence of hetero-trimeric complexes consisting of HOX, PBX and MEIS1 proteins. Experimental depletion of MEIS1 in laboratory models of MLL-AF9 leukemia indicates that this complex in turn regulates mitochondrial oxidative respiration and the expression of HLF.




MLL-fusion proteins (eg. MLL-AF9), up-regulate the expression of genes such as MEIS1, PBX and HOX. Previous studies showed the presence of hetero-trimeric complexes consisting of HOX, PBX and MEIS1 proteins. Experimental depletion of MEIS1 in laboratory models of MLL-AF9 leukemia indicates that this complex in turn regulates mitochondrial oxidative respiration and the expression of HLF.
 











  

Langerhans Cell Histiocytosis

LCH is characterized by pathologic accumulation of cells that resemble normal tissue Langerhans cells. The disease most commonly manifests as lytic lesions in bones or an eczema-like rash, but in some children it can cause major complications such as liver cirrhosis, pituitary dysfunction leading to diabetes insipidus, or progressive neurodegeneration. Recent studies revealed the presence of oncogenic mutations in the BRAF gene (BRAF-V600E) in 50-60% of LCH tumors. We and others recently found mutations in the gene MAP2K1 in LCH biopsies that did not carry mutations in BRAF. The MAP2K1 gene encodes the protein MEK which is a downstream target of BRAF. These studies indicate that activation of the BRAF-MEK-ERK pathway is central to the pathogenesis of LCH. In ongoing studies, we are investigating the role of MAP2K1 mutations in the pathogenesis of LCH. Additionally, we are studying the biochemical mechanisms by which these mutations lead to constitutive activation of the MEK enzyme.

 

Langerhans Cell Histiocytosis