Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML
Por:
Fabian-Morales, Eunice, Vallejo-Escamilla, David, Gudino, Adriana, Rodriguez, Alfredo, Gonzalez-Barrios, Rodrigo, Rodriguez Torres, Yameli L., Castro Hernandez, Clementina, Torre-Lujan, Alfredo H., Oliva-Rico, Diego A., Ornelas Guzman, Erandhi C., Lopez Saavedra, Alejandro, Frias, Sara, Herrera, Luis A.
Publicada:
1 may 2022
Resumen:
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined
by the presence of t(9;22) translocation whose origin has been
associated with the tridimensional genome organization. This
rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a
chimeric protein with constitutive kinase activity. Imatinib, a tyrosine
kinase inhibitor (TKI), is used as a first-line treatment for CML,
though similar to 40% of CML patients do not respond. Here, using
structured illumination microscopy (SIM) and 3D reconstruction, we
studied the 3D organization patterns of the ABL1 and BCR genes, and
their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML
patients that responded or not to TKI. We found that TKI resistance in
CML is associated with high levels of structural disruption of CT9 and
CT22 in CD34+ cells, increased CT volumes (especially for CT22),
intermingling between CT9 and CT22, and an open-chromatin epigenetic
mark in CT22. Altogether our results suggest that large-scale disruption
of CT9 and CT22 correlates with the clinical response of CML patients,
which could be translated into a potential prognostic marker of response
to treatment in this disease and provide novel insights into the
mechanisms underlying resistance to TKI in CML.
Filiaciones:
Fabian-Morales, Eunice:
Univ Nacl Autonoma Mexico, Doctorado Ciencias Biomed, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Vallejo-Escamilla, David:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Gudino, Adriana:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Rodriguez, Alfredo:
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Inst Nacl Pediat INP, Mexico City, DF, Mexico
Gonzalez-Barrios, Rodrigo:
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Rodriguez Torres, Yameli L.:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Castro Hernandez, Clementina:
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Torre-Lujan, Alfredo H.:
Inst Nacl Cancerol INCan, Dept Hematol, Mexico City, DF, Mexico
Oliva-Rico, Diego A.:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Ornelas Guzman, Erandhi C.:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Lopez Saavedra, Alejandro:
Univ Nacl Autonoma Mexico, Red Apoyo Invest RAI, Inst Nacl Cancerol INCan, Unidad Aplicac Avanzadas Microscopia ADMiRA, Mexico City, DF, Mexico
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Frias, Sara:
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Inst Nacl Pediat INP, Lab Citogenet, Mexico City, DF, Mexico
Herrera, Luis A.:
Inst Nacl Cancerol INCan, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Dept Med Genom & Toxicol Ambiental, Inst Invest Biomed, Ciudad Univ,Apartado Postal 70228, Mexico City, DF, Mexico
Inst Nacl Med Genom INMEGEN, Mexico City, DF, Mexico
hybrid, All Open Access; Hybrid Gold
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