RESEARCH

Our Research

Disordered Gene Regulation In Leukemia

Despite remarkable recent progress in cataloging the genomic changes associated with hematologic malignancies, we do not understand how many “driver” mutations contribute to disease development nor how they combine with other alterations to result in leukemia. We have implicated the nucleosome binding protein HMGN1, a target of recurrent amplification in leukemia, as a myeloid and lymphoid leukemia oncogene that causes widespread epigenetic alterations including global changes in histone H3 lysine 27 acetylation and methylation at stem cell genes (PMID: 32179749, 30428356, 24747640). HMGN1 is overexpressed in Down syndrome-associated leukemia (ALL), and in other ALLs and AMLs by copy number gain of chr.21 (aneuploidy or focal 21q22 amplification). We are working to understand how nucleosome modifications alter hematopoietic stem and progenitor cell epigenetics and drive acute leukemias.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

BPDCN is a highly aggressive hematologic malignancy of plasmacytoid dendritic cells, related to AML, which exhibits both skin and bone marrow involvement. BPDCN has no standard therapy and is nearly uniformly fatal within two years from diagnosis (PMID: 31243042). The genetic and epigenetic alterations driving BPDCN are not well understood. We are studying the genomics of BPDCN and modeling how specific somatic alterations, including RNA splicing factor and heterotrimeric G protein mutations, contribute to dendritic cell transformation. We discovered that BPDCN is highly and uniquely dependent on the antiapoptotic protein BCL2 for survival, and that BPDCN is markedly sensitive to BCL2 inhibition with venetoclax (PMID: 27986708). We are leading clinical trials of venetoclax in BPDCN and testing patient samples from those trials in the laboratory. We performed single cell RNA sequencing and metagenomics in BPDCN to understand disease biology (PMID: 3082768, 32182365). We are also conducting clinical trials in patients with BPDCN and we led a multicenter trial testing the CD123/IL3 receptor-targeting immunotoxin SL-401(tagraxofusp) that led to the first ever FDA approval for patients with BPDCN (PMID: 31018069, 30785714). We determine how AMLs and BPDCNs become resistant to tagraxofusp via downregulation of the diphthamide synthesis pathway (PMID: 31437130 ). This led to a new clinical trial combining tagraxofusp with azacitidine and venetoclax in AML, MDS, and BPDCN.

Sex Bias In Cancer

150,000 more men get cancer yearly in the US than women. Most individual cancer types have a male bias, including leukemia and some like BPDCN, kidney cancer, and bladder cancer that are >2:1 M:F biased. We recently examined male bias in cancer mutations across >4100 patient’s tumors and discovered a new type of tumor suppressor gene that we called Escape from X-Inactivation Tumor Suppressor (EXITS) genes (PMID: 27869828). Female cells express two copies of these genes, whereas males only express one. Therefore, female cells are relatively protected from cancer because they require two mutations to inactivate these genes, while males only need one.

Clonal Dominance In Hematopoiesis And Malignancy

The epigenetic and genetic changes referenced above in acute leukemia and BPDCN, among many others, often confer a clonal advantage to hematopoietic stem and/or progenitor cells in the absence of overt malignancy. Clonal hematopoiesis can progress to myelodysplasia (MDS) and to acute leukemia. We are developing in vivo model systems to understand how these changes gain a selective advantage, and we are using those platforms to develop therapies to target clonal dominance that may avert or delay progression to cancer. We are particularly interested in heterotrimeric G protein contributions to hematologic malignancy as the alpha and beta subunits are recurrently mutated in clonal hematopoiesis, MDS, and both myeloid and lymphoid malignancies (and in many solid tumors). We recently discovered and determined the mechanism of transformation by GNB1 and GNB2 mutations seen in BPDCN, MDS, AML, lymphoma, and leukemia (PMID: 25485910).