miR-150: targeting MLL leukemia

It has been a tough challenge to hunt for effective therapeutic targets for acute leukemia bearing mixed lineage leukemia (MLL) fusion genes. The MLL gene which maps to human chromosome 11 band q23 (11q23) is frequently involved in chromosome translocations in around 10% of total leukemia, including 5-10% of patients with acute myeloid leukemia (AML) and 80% of infant acute leukemia. The critical feature of MLL-rearrangements is the generation of a chimeric transcript consisting of 5' MLL and 3' sequences of the partner gene; at present, more than 100 different loci which translocate to the MLL gene have been identified and more than 60 different partner genes have been cloned [1]. MLL-rearranged leukemia is usually associated with intermediate to poor prognosis and refractory to conventional therapies [1]. Therefore, it is urgent to develop new therapeutic methods which have high efficacy and low side-effects to treat MLL-rearranged leukemia. These MLL-fusions are the " drivers " that determine the pathogenesis of the MLL-associated leukemias. Several important oncogenes (e.g. homeobox A (HOXA) genes, MEIS1, FLT3, MYB and MYC, etc.) serve as direct or indirect downstream targets of MLL-fusion proteins and are frequently up-regulated in MLL-associated leukemias. In addition to sharing a common driver and contributing to the pathogenesis of MLL-fusion-induced leukemia, these oncogenes have complex mutual regulatory influences on each other. For example, the HOXA cluster genes are the most well-defined direct targets of MLL fusions; MYB is an essential downstream target of the HOXA9/ MEIS1 signaling, and an autoregulatory feedback loop was reported recently in which MYB binds MLL through MENIN and regulates expression of HOXA9/ MEIS1 directly [2]; MYC, a potent oncogene which transcriptionally activates many tumor-promoting genes [3], is a downstream target gene of MLL fusions and FLT3 [4]; LIN28 is a direct target of MYC [5]. Taken together, a functional circuit, " driven " by MLL-fusions and involving all the above oncogenes (i.e. HOXA9, MEIS1, FLT3, MYB and MYC), exists in MLL-associated leukemia. However, how the MLL-pathway is regulated is unclear and this question merits deep exploration. MicroRNAs (miRNAs), a class of small (22~25 bp) non-coding RNAs important in mediating post-transcriptional gene silencing, are involved in the pathogenesis of various types of cancers [1]. Jiang et al. [6] recently show that miR-150, a miRNA significantly down-regulated in most AML cases, is up-regulated by MLL-fusion/MYC at the primary transcription level but strikingly, is repressed by MYC/LIN28 during the maturation process. …