Molecular characterization and clinical impact of t(11;15)(q23;q14-15) MLL-CASC5 rearrangement

The dynamic protein Knl1 – a kinetochore rendezvous

“…Knl1, the largest subunit of the KMN network, is required for accurate chromosome segregation during mitosis (Desai et al, 2003), and for both activating and inactivating the spindle assembly checkpoint (SAC), a conserved signaling cascade that delays anaphase onset in the presence of unattached or improperly attached chromosomes (Kiyomitsu et al, 2007;Meadows et al, 2011;Rosenberg et al, 2011;Espeut et al, 2012). Defects in Knl1 function have been implicated in genome instability, leukemia, microcephaly and neurological disorders (Kiyomitsu et al, 2007;Kiyomitsu et al, 2011;Yang et al, 2014;Genin et al, 2012). Interestingly, the phenotype observed in cells in which Knl1 is depleted is similar to that associated with the suppressed expression of the mitotic checkpoint proteins Bub1 and BubR1 (Kiyomitsu et al, 2007;Kiyomitsu et al, 2011;Cheeseman et al, 2006;Cheeseman et al, 2008), suggesting that a major function of Knl1 is to coordinate Bub1 and BubR1 signaling, a notion that has seen significant support from a number of recent studies in yeasts, Caenorhabditis elegans, Drosophila melanogaster and cultured human cells (Desai et al, 2003;Cheeseman et al, 2008;Schittenhelm et al, 2009;Venkei et al, 2012;Varma et al, 2013; reviewed by .…”

KNL1 (cancer susceptibility candidate 5)

“…KMT2A, (previous symbol: mixed leukemia gene (MLL)) is translocated with KNL1 (previous symbol CASC5, originally described as AF15q14), which makes research of published cases often arduous. t(11;15)(q23;q15) and/or KMT2A/KNL1 t(11;15)(q23;q14-15) Data on 16 cases with a t(11;15)(q23;q14-15), according to (Yang et al, 2014) are the following: there was 2 of myelodysplastic syndrome (MDS) cases, 10 acute myeloid leukemia (AML) cases (2 M1, 4 M2, 3 M4, and 1 NOS), and 4 acute lymphoblastic leukemia (ALL) cases. Mean age of the patients was 20.6 years (range 1-54); there were 11 males and 5 females.…”

“…Out of 8 patients for whom clinical data were available, only 3 are in complete remission, whereas 5 patients died with a mean survival period of 10.4 months. t(11;15)(q23;q15) and KMT2A/KNL1 Of 7 cases with a t(11;15)(q23;q15) and KMT2A/KNL1 hybrid gene and fusion protein ((Chinwalla et al, 2003;Kuefer et al, 2003;Meyer et al, 2006;Yang et al, 2014). Diagnosis was: therapy related MDS (t-MDS) in 2 cases, AML in 4 cases (1 M2, 2 AML-M4, 1 AML-NOS), and 1 de novo T-ALL.…”

D40/KNL1/CASC5 and autosomal recessive primary microcephaly

“…Chromosomal translocations of KNL1 with MLL gene were observed in several cases of leukemia. Two cases of the translocation involve exon 11 of KNL1 gene and one case in intron 11 (Hayette et al ; Chinwalla et al ; Kuefer et al ; Yang et al ). Like the cases of other genes fused with MLL, it is reasonable to speculate that disruption of MLL protein rather than KNL1 is important in tumorigenesis of lymphocytes.…”