MLL a SET domain histone methyltransferase that catalyzes

MLL associated
translocations are found in 70% of infant leukaemia’s less than 2 years of age1. Normally, the MLL gene encodes
for a SET domain histone methyltransferase that catalyzes histone H3 lysine 4
methylation at particular regions and in mixed lineage leukemia, the catalytic
SET domain responsible for H3K4 methyltransferase property is lost and the
remaining MLL protein is fused  to a
variety of partners such as AF4, AF9, ENL and AF10 by chromosomal
translocations in a balanced manner which causes the overexpression of leukemia
promoting genes2.Various cellular proteins like
PI3K, GSK3?, mTOR, cyclin dependent kinases, histone deacetylases and histone
methyltransferases are targeted for the treatment of mixed lineage leukemia.

Keywords-Mixed
lineage leukemia, translocation,histone methyltransferase, apoptosis, differentiation

I. Introduction

Mixed Lineage Leukemia pathology associated with
haemopoetic cells is under a hot bebate from the last two decades. MLL
associated translocations are found in 70% of infant leukaemia’s under the age
of 2 years with a very poor prognosis1. Mixed lineage
leukemia display co-expression of lymphoid as well as myeloid antigens hence
infants with MLL translocation show both myeloid and lymphoid blast cell
population3. Normally, the
MLL gene encodes for a SET domain histone methyltransferase that catalyzes the
methylation of lysine 4 of histone H3 (H3K4) at particular regions 4. In MLL, the catalytic
SET domain responsible for H3K4 methyltransferase activity is lost and the
remaining MLL protein is fused  to a
variety of partners such as AF4, AF9, AF10 and ENL by balanced chromosomal translocations
and rearrangements2. Amino terminal
portion of MLL protein is fused to fifty distinct binding partners 5.The fusion
products retain the abilty to locate gene specific recognition regions  even after translocation and interact directly
or  indirectly with other histone
methyltransferaes like DOTIL6. DOT1L
interacts with six unique MLL fusion proteins created by chromosomal translocations
i.e. MLL-AF4, MLL-AF9, MLL-ENL, MLL-AF10, SET-NUP214, CALM-AF107.The fusion
products gain the ability to recruit Dot1L to the aberrant gene regions and
increase the expression of genes responsible for promotion of  leukaemia 8.There is still
lack of good quality therapeutics for mixed lineage leukemia due to lack of
small molecule inhibitors that will directly target MLL9.The focus of
the review will be on the recent published work as well as therapeutic targets
from the last 2 decades.

II.
PI3K as a therapeutic target of MLL

Recent
reports have shown that Simaltaneous inhibition of  PI3K/mTOR  has shows anticancer activity in MLL
rearranged leukaemias10. In vivo
PI3K/mTOR inhibition has shown to  reduce
tumour progression and also shown to increase survival in MLL-AF9 xenograft
mouse model10.BEZ, rapamycin
and MK-2206 have shown good in vitro activity as well as have shown good
activity in mice tumour models by inhibiting PI3K, mTOR and AKT pathways10. 

III.
CDK4/CDK6 as a therapeutic target of MLL

In
MLL there is a cell differentiation block which can be broken by using small
molecules like CDK6 inhibitors11.CDK6 as a
therapeutic target for mixed lineage leukemia was identified by Plakle et al.,
201412. PD-0332991 is a dual
inhibitor of CDK4/CDK6 which is clinical trials for  treatment of breast cancers as well as
PD-0332991 have shown strong growth inhibition in MLL rearranged  leukemic cells 12. Current
treatment of MLL is chemotherapy and allogenic stem cell transplantation in
selected cases13.

IV.
Small molecule inhibitors of histone deacetylases as treatment of MLL

It
has  been shown recently that  HDAC inhibitors induce   apoptosis
in MLL rearranged cell by autophagy 14. Inhibition of
histone deacetylase by VPA (valproic acid) in cells  harbouring MLL induced cell cycle arrest
(G1-phase) and apoptotic cell  death  in MLL-AF9 expressing cell lines15.

V.
Retinoic acid and Vitamin D as important drugs for MLL

MLL-AF9 expressing leukemic cell line MOLM-14
undergoes differentiation when exposed to ATRA or 1, 25-dihydroxyvitamin D316.  Simultaneous
treatment of MLL cells with Retinoic acid and epidrug 5-azacytidine has shown
to inhibit growth of  MLL positive
leukemic cells17

VI.
Glycogen Synthase kinase 3 is an important target to control MLL

Glycogen
Synthase kinase3 has shown to  support
MLL leukemia proliferation18.GSK3 inhibition
has shown to induce G1 growth  arrest and
cell death  in MLL transformed cells18. GSK3-?
inhibition has shown to increase survival in mouse model of MLL associated leukaemic
18. Specific GSK-3 inhibitor
SB-415286 has been repored to inhibit growth  by induction of  apoptosis in leukemic cells19.

VII.Combination
of Sirt1 activators and DOT1L inhibitor for the treatment of mixed lineage
leukemia

Activation
of SIRT1 and at same time inhibition of DOTIL has been shown  be an effective therapy for mixed lineage leukemia20.SIRT1
activation  mediated silencing of the
MLL-AF9 leukemia has been shown to be  enhanced by simultaneous DOT1L inhibition20.SIRT1 activator
SRT1720 in combination with DOTIL inhibitor augment has been reported  to cause apoptosis induction in mixed lineage
leukemia cells20.

VIII. ?-catenin as a therapeutic target of MLL

It has been reported  that Leukemic stem cells have a more  self renewal and drug résistance property 21. ?-catenin establishes the growth of mixed
lineage  leukemia  Leukemic stem cells22. Reversal of LSC to PLSC has shown to significantly
reduces the growth of  mixed lineage
leukemia  cells by  ?-catenin downregulation or  suppression  23.