Leticia Fröhlich Archangelo
Ms 3

Tel.: (16) 3315-3118


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General outline

Somatic mutations in several components of the spliceosome machinery have been recently implicated in cancer. Our main interest is to investigate the functional consequence of recurrent, yet uncharacterized, splicing factor mutations and/or aberrant expression in hematological and solid tumors. In order to reach our goal, we make use of in silico mutational analysis, we retrovirally express (the mutated and wild type genes), silence (shRNA) and disrupt (gRNA) the genes of interest in cancer cells, and assess the effect of its aberrant expression or mutations in a variety of cellular processes by in vitro and in vivo assays. 

The current projects in lab are:

1- Investigation of the participation of splicing factor regulatory kinase (KIS; UHMK1) in leukemogenesis:

Preliminary data from our group suggest the role of Uhmk1 in hematopoietic cell differentiation. Our hypothesis is that by phosphorylating its target splicing factors, Uhmk1 affects splicing and gene expression of important genes for differentiation of hematopoietic cells. To assess this issue we are currently investigating Uhmk1 regulatory network by gene expression (RNAseq) and phosphoproteome of Uhmk1 overexpressing and knock-down cells. 

2- Functional characterization of SF1 mutations described in cancer patients.

The SF1 protein recognizes the introns 3′ regions during early stages of the spliceosome formation. Somatic mutations in SF1 were described in a subset of patients with different types of cancer. We mapped the spectrum of SF1 mutations in cancer patients and are currently evaluating the functional consequence of SF1 inhibition and overexpression, as well as the impact of its mutations in cancer cell lines. 

Other projects in the lab:

3- Investigation of cooperative oncogenes to IL7R mutations in acute leukemias:

Mutations in the interleukin 7 receptor (IL7R) gene result in constitutive activation of this receptor and its signaling pathway. Our group is interested in identifying genetic alterations that cooperate with IL7R mutations to promote the malignant phenotype. To this end, wild type and mutated IL7R-bearing Ba/F3 strains are transduced with secondary genetic lesions and assessed for accelerated growth and increase in malignant phenotype in vitro and in vivo.  

4- Characterization of the PICALM interacting mitotic regulator (PIMREG) in the progression and therapy response of glioblastoma cells:

PIMREG is highly expressed in cancer cell lines and its protein levels strongly correlate with cellular proliferation in both malignant and normal cells. Among all tumor types, the highest levels of its transcripts are observed in Glioblastoma Multiform (GBM). Our preliminary data indicates that PIMREG is induced upon treatment of GBM cells with genotoxic agents. We are currently investigating the role of PIMREG in the control of proliferation, replication and possibly, DNA damage response in GBM cells.



1- Campos, L.W., Zenatti, P.P., Pissinato, L.G, Rodrigues, G.O.L, Artico, L.L, Guimarães, T.R, Archangelo, L. F., Martínez, L, Brooks, A.J., Yunes, J.A. (2019) Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7Rα cause receptor hypersensitivity. BLOOD, v. 1, p. blood-2018-09-872945. doi: 10.1182/blood-2018-09-872945.

2- Barbutti, I., Machado-Neto, J., Arfelli, V., Campos, P., Traina, F., Saad, S.T.O, Archangelo, L.F. (2018) The U2AF homology motif kinase 1 (UHMK1) is upregulated upon hematopoietic cell differentiation. Biochim Biophys Acta. doi: 10.1016/j.bbadis.2018.01.004. 

3- Arfelli, V.C.; Archangelo, L.F. UHMK1 (U2AF homology motif kinase 1); Atlas Genet Cytogenet Oncol Haematol. 2018; 22(8):328-335. 

4- Archangelo, L.F. PIMREG (PICALM interacting mitotic regulator); Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):358-362.

5- Barbutti, I., Xavier-Ferrucio, J.M., Machado-Neto, J.A., Ricon, L., Traina, F., Bohlander, S.K., Saad, S.T.O. and Archangelo L.F. (2016) CATS (FAM64A) abnormal expression reduces clonogenicity of hematopoietic cells. Oncotarget, 7:68385-68396.  

6- Archangelo, L.F., Greif, P.A., Maucuer, A., Manceau, V., Koneru, N., Bigarella, C.L., Niemann, F., dos Santos, M.T., Kobarg, J., Bohlander, S.K., Saad S. T. O. (2013) The CATS (FAM64A) protein is a substrate of the Kinase Interacting Stathmin (KIS). Biochimica et biophysica acta, 1833, 1269-1279.

7- Archangelo, L. F., Greif, P., Holzel,  M., Harasim, T., Kremmer, E., Przemeck, G., Eick, D., Deshpande, A., Buske, C, Deangelis, M. H., Saad S. T. O., Bohlander S. K. The CALM and CALM/AF10 interactor CATS is a marker for proliferation. Molecular Oncology., v.2, p.356 – 367, 2008.

8- Archangelo, L.F., Glasner, J., Krause, A. and Bohlander, S.K. (2006) The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10. Oncogene, 25, 4099-4109. 


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