Tianxiang Hu, PhD
The researches in our group focus on the investigation of molecular mechanisms regulating leukemia initiation and progression. We decipher the transcriptional regulatory network, including oncogenes, miRNAs and lnRNAs during leukemogenesis driven by different chromosome translocations. We also investigate the gene regulation underlying the establishment of immune evasion in leukemogenesis. We use the newly discovered insights to direct the development of novel cancer therapy strategies.
Hematologic malignancies associated with FGFR1 abnormalities present in heterogeneous forms, including myeloproliferative neoplasm, acute myeloid leukemia (AML), T- or B-lineage lymphoblastic leukemia/lymphoma, and even mixed phenotype acute leukemia.
Also known as Stem Cell Leukemia/Lymphoma syndrome (SCLL), the hallmark of this disease is the presence of chimeric kinases formed as a result of chromosome translocations. By performing bone marrow transduction and transplantation, we have developed syngeneic mouse models of this disease with mouse bone marrow cells in BALB/c mice, and human cell models with CD34+ hematopoietic stem cells in immunocompromised NSG mice, to investigate molecular mechanisms regulating leukemia initiation and progression. Current specific research interests include:
miRNAs have pathogenic roles in the development of a variety of leukemias. In an effort to discover the critical roles of miRNAs in the disease progression of SCLL, we carried out a comparison of differentially expressed miRNA in normal counterparts and SCLL cells, we identified the miR-17/92 cluster and miR-339 are direct targets of FGFR1 fusion kinase. Through combined target prediction, luciferase reporter assay and western blotting, we showed that miR-17/92 promoted cell proliferation and survival by targeting CDKN1A and PTEN in B-lymphoma cell lines and primary tumors, while miR-339 promoted development of Stem Cell Leukemia/Lymphoma syndrome via downregulation of the BCL2L11 and BAX pro-apoptotic genes. The report about miR-339 is the first one to demonstrate its oncogenic effect in cancer.
In an attempt to understand how FGFR1 fusion kinase activate the expression of c-Myc oncogene, we revealed a novel functional model of FGFR1 fusion kinase, in which the full length cytoplasm-restricted chimeric kinases activated cytoplasmic signaling pathways like STAT5, to indirectly activate c-Myc expression, while a truncated form of nucleus-restricted FGFR1, generated by granzyme B cleavage of the chimeric kinases, could bind directly to MYC regulatory regions and activate its expression. In addition, we revealed the disease contribution from fusion partner gene BCR in BCR-FGFR1 driven SCLL, which is the most aggressive subtype of SCLL. With a combination of in vitro proteomic analysis with reverse phase protein array of transformed cell lines and in vivo bone marrow transduction and transplantation experiment in mouse model, we discovered that the BCR serine-threonine kinase activated the Shp2 kinase to promote leukemogenesis. This work rationalizes the necessity in developing precision therapeutics that target the consequences of the fusion partner together with the consistent aspect of the chimeric genes in chromosome translocations related leukemia.
In Collaboration with Dr. David A. Williams in Harvard Medical School, we investigated the role of Rac1/2, two important members of the Rho GTPases family, in FGFR1 fusion kinase driven SCLL, and revealed that Rac1/2 knockout led to impaired leukemia progression through reduction of leukemia stem/progenitor cell homing and proliferation ability. Moreover, we demonstrated in BCR-FGFR1 fusion mouse model that the GFE domain attenuated leukemia progression through the RhoA/Rock/Pten signaling axis. Loss of the GEF domain or knockdown of RhoA enhanced cell proliferation and invasion potential, resulted in increased leukemogenesis. Regarding the mechanism, loss of the GEF domain suppressed activation of RHOA and PTEN, leading to increased activation of AKT. This can also be the same case for the distinct disease progression caused by the two isoforms p210 and p190 of BCR-ABL1, considering the similar exclusion of the GEF domain in p190.