Pediatric malignancies frequently harbor chromosome-arm level copy number changes that potentially impact the expression level of a large number of genes, yet how segmental alterations contribute to tumorigenesis remains poorly defined. This is a major gap in our understanding of the pathogenesis of childhood cancers and hampers the rational design of new therapies. One such deletion is loss of part or all of chromosome 7 [-7/del(7q)], the most common cytogenetic abnormality in myeloid malignancies of childhood. -7/del(7q) occurs in up to 33% of juvenile myelomonocytic leukemias (JMML), which are aggressive myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) characterized by RAS pathway mutations and few other somatic alterations. In myeloid malignancies, -7/del(7q) is associated with treatment resistance and a poor prognosis for reasons that are not understood. The long-term goal of this proposal is to understand the molecular pathogenesis of -7/del(7q) and to reveal new therapeutic targets for JMML patients. In previous work, we reported that the transcription factor, CUX1, is a highly conserved myeloid tumor suppressor gene encoded on 7q. We demonstrated a striking association of oncogenic RAS pathway mutations with CUX1 deletions across tumor types. We recently engineered a Cux1 knockdown mouse model (Cux1low), which develops a spontaneous MDS/MPN with features of human JMML, including myelomonocytic expansion in all hematopoietic compartments with infiltration into non-hematopoietic tissues, dysplasia in all myeloid lineages, and anemia. In addition to CUX1, 7q deletions are typically large and span other established or putative tumor suppressor genes and/or myeloid regulators. In this proposal, we will test the hypothesis that 7q is a `Contiguous gene syndrome' region, wherein combined dosage imbalance of multiple genes drives JMML, in combination with oncogenic RAS signaling. We will use our unique mouse model and CRISPR/Cas9 genome editing to achieve the following Specific Aims: 1) Identify the cellular and molecular mechanisms by which Cux1 knockdown and Ras cooperate in JMML; 2) Define the pathogenesis of combinatorial dosage imbalance of 7q genes in JMML. This work will have a positive impact on the field of myeloid malignancies by: i) elucidating the molecular mechanisms by which combinatorial loss of 7q genes drives disease; ii) identifying new molecular targets for the treatment of JMML; and iii) establishing a physiologically accurate mouse model in which novel therapies for human disease can be rapidly tested and optimized. Our mouse model of JMML will fulfill a major unmet need for childhood myeloid malignancies, specifically a preclinical mouse model for screening of approved and experimental drugs in future studies. Our work will reveal the relevant proliferative and differentiation pathways for therapeutic targets to test in this model.
Deletion of part or all of chromosome 7 is a common cytogenetic abnormality in aggressive childhood myeloid malignancies, including juvenile myelomonocytic leukemia, inherited cancer predispositions, and in cancer survivors, yet the critical genes on chromosome 7 have remained unclear. We identified a gene on chromosome 7, CUX1, to be a regulator of blood cell growth, and mice with Cux1 deficiency spontaneously develop myeloid malignancies. In this proposal, we will identify the other genetic changes that cooperate with Cux1 in leukemia development, the mechanism by which these genetic changes interact together to drive disease, and reveal new pathways to therapeutically target in patients with these fatal leukemias.
