Noncoding RNAs and CLL: challenges for future investigations
| Challenge . | Comments . |
|---|---|
| Does CLL develop in knockout mouse models of miR-15/miR-16, and is it indolent or aggressive? | If yes, this will be the ultimate confirmation that this cluster is causally involved in the initiation of CLL. Presumably the miR-15a/miR-16-1 knockout will develop the indolent form of CLL like the NZB mice. The presence of various long ncRNAs in the same deleted chromosomal region as well as an independent, highly similar cluster on chromosome 3 that is rarely deleted in patients with CLL might be a challenge to this in vivo approach. In addition, does aggressive CLL develop in other mouse models, such as knockout models for the miR-29 or miR-181 family? |
| Does CLL predisposition result from sequence variations in miRNA interactor sites? | The high number of germline DNA sequence variations linked with low levels of predisposition to CLL offer the basis for this investigation. |
| MiRNAs as plasma/serum markers for diagnosis, prognosis, and response to therapy in patients with CLL. | Although technically feasible, such studies would involve thousands of patients and, more important, equal numbers of controls. The levels of expression of various miRNAs in the normal population are largely unknown. For example, are the miRNA expression levels in serum and/or plasma in a 20-year-old white man the same as those in a 60-year-old African American woman? |
| Should miR-15/miR-16 expression levels be increased in patients with aggressive CLL? | Most aggressive CLLs are derived from indolent cases. Thus it is possible that loss of miR-15a/miR-16-1 cooperates with TCL1 overexpression in causing or contributing to the aggressive form of CLL. Thus it seems possible that introduction of miR-15/miR-16 into aggressive CLLs will be beneficial. |
| Because studies have already found that networks of interacting ncRNAs function in CLL pathogenesis, should we try to identify the ncRNAs involved in response of CLL to therapy? | The possibility that aberrations in these ncRNAs together with aberrations in PCGs can explain the failure of current chemotherapy regimens to cure CLL should be considered. |
| Challenge . | Comments . |
|---|---|
| Does CLL develop in knockout mouse models of miR-15/miR-16, and is it indolent or aggressive? | If yes, this will be the ultimate confirmation that this cluster is causally involved in the initiation of CLL. Presumably the miR-15a/miR-16-1 knockout will develop the indolent form of CLL like the NZB mice. The presence of various long ncRNAs in the same deleted chromosomal region as well as an independent, highly similar cluster on chromosome 3 that is rarely deleted in patients with CLL might be a challenge to this in vivo approach. In addition, does aggressive CLL develop in other mouse models, such as knockout models for the miR-29 or miR-181 family? |
| Does CLL predisposition result from sequence variations in miRNA interactor sites? | The high number of germline DNA sequence variations linked with low levels of predisposition to CLL offer the basis for this investigation. |
| MiRNAs as plasma/serum markers for diagnosis, prognosis, and response to therapy in patients with CLL. | Although technically feasible, such studies would involve thousands of patients and, more important, equal numbers of controls. The levels of expression of various miRNAs in the normal population are largely unknown. For example, are the miRNA expression levels in serum and/or plasma in a 20-year-old white man the same as those in a 60-year-old African American woman? |
| Should miR-15/miR-16 expression levels be increased in patients with aggressive CLL? | Most aggressive CLLs are derived from indolent cases. Thus it is possible that loss of miR-15a/miR-16-1 cooperates with TCL1 overexpression in causing or contributing to the aggressive form of CLL. Thus it seems possible that introduction of miR-15/miR-16 into aggressive CLLs will be beneficial. |
| Because studies have already found that networks of interacting ncRNAs function in CLL pathogenesis, should we try to identify the ncRNAs involved in response of CLL to therapy? | The possibility that aberrations in these ncRNAs together with aberrations in PCGs can explain the failure of current chemotherapy regimens to cure CLL should be considered. |