Hematology News

Novel insights on TLX1 function in T-ALL pave the way towards differentiation therapy Kim De Keersmaecker 1,2 1Center for Human Genetics, K.U.Leuven, Leuven; 2Center for the Biology of Disease, VIB, Leuven, Belgium doi:10.3324/haematol.2012.070227

he mutational landscape of T-cell tumors. 4,5 Furthermore, they observed and LEF1 were identified as master reg - acute lymphoblastic leukemias that TLX1 tumor cells show defective ulators acting downstream of TLX1 and (T-ALL) has been intensively activation of the mitotic checkpoint due TLX3 and these factors are down-regu - T 5 studied over the past decades and we to downregulation of mitotic checkpoint lated by TLX in T-ALL. These now have an extensive list of genetic in TLX1 pre-leukemic cells. These results make it tempting to speculate defects that can occur in these tumors. 1 observations can be linked to the aneu - that inactivation or downregulation of Central to T-ALL pathogenesis is the ploidy that is seen in TLX1 positive RUNX1 and LEF1 is an alternative NOTCH1 signaling cascade which is mouse and human tumors. 4 and/or co-operating mechanism in T- hyperactivated in more than 50% of T- Now a study by Dadi et al. also pro - ALL to impair TCR α rearrangement. ALLs. 2,3 In addition, T-ALL cells are char - vides clues on how TLX1 hijacks T-cell These novel insights into the action acterized by chromosomal rearrange - differentiation and mediates the charac - mechanism of TLX factors in T-ALL ments that juxtapose transcription fac - teristic early cortical maturation block open up new opportunities for thera - tor genes such as TLX1 (also called in TLX + T-ALL patients. 6 They show peutic design in TLX + T-ALL. Dadi and HOX11), TLX3 (also called HOX11L2) that the TCR α locus in TLX + T-ALLs is colleagues nicely show that downregu - or TAL1 to strong promotor and characterized by the repressive lation of TLX proteins in TLX+ T-ALL enhancer elements, resulting in overex - H3K37me3 histone modification and cell lines abolishes the cellular differen - pression of these oncogenic transcrip - that TLX1 inhibits TCR α rearrange - tiation blockage and induces cell death; tion factors. ment by binding the ETS1 transcription effects that could also be obtained by These rearrangements and resulting factor and repressing TCR α enhancer overexpression of TCR αb in overexpression in T- activity. As a consequence, T cells with TLX + cells. 6 Although there is still a long ALL have been known for many years. an unsuccessful rearranged TCR α locus way to go before suitable small mole - However, first insights into the onco - cannot continue their development and cule drugs are identified, these results genic mechanism of TLX1 in T-ALL are blocked at this stage of differentia - pave the way for ‘differentiation treat - have only recently been obtained. The tion. Interestingly, RUNX1/AML1 and ment’ in TLX + T-ALL. Such treatment Ferrando group showed that mice with LEF1, two transcription factors for could abrogate the TLX mediated inhi - T-cell specific TLX1 expression develop which recently inactivating mutations bition of TCR α rearrangement and T-cell neoplasms that show a distinct in T-ALL were described, 7,5 bind the could prove to be very effective, similar expression signature characterized TCR α enhancer locus together with to the all-trans retinoic acid based dif - by down-regulated transcripts and that ETS1 and TLX1 to initiate TCR α ferentiation treatment in acute promye - are shared with human TLX positive rearrangement. Furthermore, RUNX1 locytic leukemia. 8

References ment of SET-NUP214 in T-cell acute lym - 6. Dadi S, Le Noir S, Payet-Bornet D, Lhermitte L, phoblastic leukemia. Haematologica. 2011;96 Zacarias-Cabeza J, Bergeron J, et al. TLX 1. Aifantis I, Raetz E, Buonamici S. Molecular (12):1808-14. Homeodomain Oncogenes Mediate T Cell pathogenesis of T-cell leukaemia and lym - 4. De Keersmaecker K, Real PJ, Gatta GD, Maturation Arrest in T-ALL via Interaction phoma. Nat Rev Immunol. 2008;8(5):380-90. Palomero T, Sulis ML, Tosello V, et al. The with ETS1 and Suppression of TCR α Gene 2. Weng AP, Ferrando AA, Lee W, Morris JP 4th, TLX1 oncogene drives aneuploidy in T cell Expression. Cancer Cell. 2012;21(4):563-76. Silverman LB, Sanchez-Irizarry C, et al. transformation. Nat Med. 2010;16(11):1321-7. 7. Gutierrez A, Sanda T, Ma W, Zhang J, Activating mutations of NOTCH1 in human T 5. Della Gatta G, Palomero T, Perez-Garcia A, Grebliunaite R, Dahlberg S, et al. Inactivation cell acute lymphoblastic leukemia. Science. Ambesi-Impiombato A, Bansal M, Carpenter of LEF1 in T-cell acute lymphoblastic leukemia. 2004;306(5694):269-71. ZW, et al. Reverse engineering of TLX onco - Blood. 2010;115(14):2845-51. 3. Wang Q, Qiu H, Jiang H, Wu L, Dong S, Pan J, genic transcriptional networks identifies 8. Kogan SC, Bishop JM. Acute promyelocytic et al. Mutations of PHF6 are associated with RUNX1 as tumor suppressor in T-ALL. Nat leukemia: from treatment to genetics and back. mutations of NOTCH1, JAK1 and rearrange - Med. 2012;18(3):436-40. Oncogene. 1999;18(38):5261-7.

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