Current to locate gene specific recognition regions even after

                  Current status: Mixed lineage leukemia

                     Mohd
Ishaq Dar 1, Mohd Saleem Dar 2 and Suraya Jan 3

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Abstract

MLL associated
translocations are found in 70% of infant leukaemia’s less than 2 years of age.
Normally, the MLL gene encodes for a SET domain histone methyltransferase that
catalyzes histone H3 lysine 4 methylation at particular regions.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 genes.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
population2. 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 3. 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 rearrangements4. 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 10 years.

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  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 supports MLL leukemia proliferation18.GSK3 inhibition
induces G1 growth  arrest and cell death  in MLL transformed cells18. GSK3-?
inhibition has shown to increase survival in mouse model of MLL associated leukaemic18. Specific GSK-3 inhibitor
SB-415286 inhibits growth  by induction 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 can be an effective therapy for
mixed lineage leukemia20.SIRT1
activation  mediated silencing of the
MLL-AF9 leukemia is enhanced by simultaneous    DOT1L inhibition20.SIRT1 activator
SRT1720 in combination with DOTIL inhibitor augment 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.

 

IX. TET1 is a direct target of MLL-fusion proteins and
is an important therapeutic target

TET1 has shown to be  highly  expressed  in MLL-rearranged leukemia cells with
leads  to drastic  increase of 5-hydroxymethylcytosine levels24.TET1 has shown to be an associated parter of
MLL which is leads to increased  growth 24.  Overexpressed
of TET1  in MLL rearranged leukemia has
shown to be responsible for overexpression of leukemia promoting genes Hoxa9 Pbx3
and Meis1 25.TET1 overexpression has shown  increases proliferation and inhibit cell death
of MLL cells26.Recent report suggested that TET1 knockdown
or therapeutic intervention of TET  prevent MLL rearranged leukemia27.

X.
BET family members and MLL

It has been shown that BET family members i.eBromodomainT,Bromodomain2,Bromodomain
3 and Bromodomain 4  recruit MLL fusion
oncogene proteins to diverged genic regions and increase the expression of  leukemia inducing  genes BCL2, CDK6 and C-MYC28. It has been
shown that inhibition of bromodomain proteins could provide a new novel approach
for the treatment of mixed lineage leukemia .

XI.
DOTIL inhibitors for the treatment of MLL

It has been shown that inhibition of DOTIL by small
molecules  kill mixed lineage leukemia
cells by inhibiting H3K79 hypermethylation at the promoters of leukemia
promoting genes29. Inhibition of
DOT1L has shown to  increase apoptosis in
cells carrying MLL rearrangement cells  as well as in mouse model of MLL30. EPZ5676 and
EPZ004777 are the currently available DOT1L inhibitors which are in research
and development for the treatment of mixed lineage leukemia31.

XII. Lysine specific demethylase
inhibitors for the treatment of MLL

LSD1 is shown to be  essential for 
proliferation and growth  of
leukemic stem cells containing MLL-Fused oncogenes32 LSD1 (Lysine specific
demethylase1) is shown to be  highly up
regulated in mixed lineage leukemia 32. It has been
shown that Lysine specific demethylase inhibitors  promote differentiation and apoptotic cell
death of MLL cells33.

 

XIII. Menin and MLL interaction
blockers

Borkin et al.
recently developed  potent  inhibitors  blocking interaction of leukemia associated
protein MLL and menin  34. These compounds showed to  inhibit the growth of leukemia cells in vitro
as well as prolonged the survival of MLL leukemic mice34. Inhibiting the interaction between  Menin   and MLL   has shown to cause downregulation of Hox A
genes and differentiation of MLL-Rearranged Leukemic cells34.Borkin et al.
Showed that  MI-463 and MI-503 blocked  the MLL 
Menin interaction, resulted in  increased  cell 
death and differentiation 34.

XIV. Conclusion

 

Various
small molecule inhibitors are in research and development for the treatment of
mixed lineage leukemia. All Currently available treatments for mixed lineage leukemia
have low efficacy as well as high toxicity. So there is a need to develop new
drugs as well as to identify new therapeutic targets for mixed lineage leukemia