Please do it, do it because I mean, it changed completely my
my career. And I think it's a great
opportunity, but not just for the funding itself.
That obviously is, is what we need to move forward in our
career for sure, but also for the visibility.
And because it's, it's, I mean the prestigious of these grants
is very well known in the community of hematologist.
Welcome to EHA Unplugged, the official podcast channels of the
European Hematology Association. EHA.
I am your host, Isabella Libera, and today we have the pleasure
to have with us Doctor Anario Machin.
Welcome. Thank you very much for having.
Me So Doctor Anario Machin is HPI at the Hematology
Experimental Lab, Tonoma de Madrid and she's also an
honorary lecturer at the Center for Hemato Oncology at the Barts
Cancer Institute in the Queens Mary University of London.
Her research aims to improve the understanding and management of
familial AML acute myeloid leukemia and focuses on
exploring GEM line mutations in families with AML.
Doctor Rheomachin's work has was supported by an EHA Junior
research grant. Her results have been recently
published and we will be discussing them today.
So we will start by analyzing why she's studying family and
AML, then why she has focused on a certain translocation and what
the consequences of this translocation are and how they
activate key leukemia genes. And finally, we will see how
this is clinical relevant at the moment.
So let's start by the basis, looking at the big picture, why
work in familial AML? Thank you, Mami.
There are two weeks groups of accumulated leukemia the
sporadic cases, but we are always forgetting about the
familial cases that are the ones where we are inherited A
mutation that can cause the disease.
So we this is this was recognized very recently by The
Who classification of myeloid neoblasms.
So before 2015 even if we knew that there were some aggregation
in families and nothing was really done for the diagnostic
of these of these families, we were investigating in new genes
that could be like causing this predisposition to do acute my
leukemia and other myeloid neoblasms.
So we considered that it was really, really relevant to look
into these families, identify the genetic cause of these of
these, especially at the point of the transplantation.
Because so far we know that the the cure of these patients is
the, the, the transplantation. The best donor is normally a
familiar or a relative of the of these patients.
But if the patient, if the relative has also the, the, the
jetline variant, the the recipient will develop the
disease again. So this is what we call donor
derived leukemia and is really aggressive.
So we need to avoid that. So we need to understand the
genetics behind familial cases. Then my work also focus on the
sporadic disease like so I have like a 2 main lines of research
of my research. One focus on familial cases, but
the other is in a sporadic disease like for example this
rare subtype that is the the patients with the the
chromosomal translocation between chromosome 6 and
chromosome 9. So this translocation between
chromosome 6:00 and 9:00, you say this is sporadic, it's not.
Familiar. It's not familiar.
So this creates a fusion protein.
What are the consequences of this fusion protein?
What does it do? That was exactly what we wanted
to to understand with this project because it is a
recognized subtype is again in the myeloid classification by
who? But so everybody knows that it
exists is quite a frequent, but the consequences of and the
function of this fusion gene, it was still unknown and the basics
didn't have any any specific therapy for.
So what we did know is like this.
The transportation between chromosome chromosome 6 and
chromosome 9 results in a fusion gene between the DECK gene and
Nope 214 gene. So the consequence of this
fusion gene is a chimeric protein, half of DECK and half
of Nope 214. So that was known.
But how these kinetic protein induces the development of acute
myeloid leukemia was still unknown.
And the patients, these patients with this translocation have a
really poor prognosis, especially when this
translocation occur at the same time with the fleet three IT DE
mutation that is quite frequent. Normally more than 70% of these
patients also appear these fleet 3 ITD mutation.
So they the the prognosis of these patients is really poor.
The age of the diagnosis of these patients is younger than
the average for acute malaria leukemia or they normally have a
really high rate of relapse so that because there is no
actually so they respond, but then they relapse because the
clone with the translocation is still there and it causes the
relapse of the disease. So we really wanted to
understand how this kinetic protein could induce leukemia
and if there was something that we could target to kill these
leukemic cells. So what are the targets of this
fusion protein? So the main finding of our
project and that we are really proud of is like we found that
BEKNUP 214 acts as a transcription factor.
So it binds to the regulatory region of key leukemia genes
like HOX genes or FOXY one who's an induced and these induces the
overexpression of these key leukemia target genes.
So then what we know is the overexpression of FOXY one or
HOX genes induces leukemia. So this is already known because
they are genes overexpressed in other subtypes of leukemia.
But what we identified was the what was causing this
overexpression, That was the binding of Decknum 214 to the
regulatory regions. So then understanding why these
genes are inducing leukemia, it was quite well studied before
because FOXY one for example, blocks differentiation.
But this is one of the heats that normally occur to for to
induce leukemia leukemia development.
And also as well the over expression of hoax genes that
are really, really well known targets and are over expressed
in other subtitles like the ones with KMDT to a rearrangements.
So the the novelty was identifying this new this new
role for techno 214 over expressing, inducing the over
expressing of these teams. And what it was more important
it was the the group 214 in binds to this region with the
help of XPO 1. And XPO 1 is a is a protein that
binds to the group 214 and is required these binding for the
over expression of hoax genes and FOXY one among other genes.
And it was really interesting because we had a good
representation of patients with A-69 translocation given that it
was a very rare entity. And we compare, we compare the
response of this space of this cell, the cells of these
patients with the T-69 translocation with the response
to for other AML subtypes. So we treat in all these cells
with more than 527 compounds. And it was really interesting to
find that on the top of the list.
So the the compounds that were more specific and more selective
for the T-69 patients were the XP-1 inhibitors.
So there was a clear relationship between our
finding, so identifying XPO one being super specific and
efficient for the T-69 patients compared to other AML subtypes
and the the fact that Techno 214 interacts with XPO 1.
So then we went a step forward. So we found that Techno 214
requires XPO 1 interaction to induce the best person of these
genes that I mentioned before. And when we treat the patient
cells with XP-1 inhibitors, this binding is lost.
And this the expression of these key leukemia genes was reduced
causing the the the the kill of the of these cells, leukemia
cells. So in a in a way we identify a
potential targeted therapy 46, nine patients so.
That would be my question. Can you use this XPO 1
inhibitors in patients? Is it known whether this is safe
to use and? That's, that's a very
interesting question because XP-1 inhibitors 11 cellinexor
for example, is an XP-1 inhibitor approved for the
treatment of multiple myeloma, which is great because it's
approved already. So it will speed up the the the
possibility of use of being used for acute minor leukemia
treatment however is very toxic. So there are new versions of XPO
1 inhibitors coming now and being studied in preclinical and
clinical studies. So probably in the in the coming
years, we will have more safe XPO 1 inhibitors that can be
definitively be tested. So I believe our research will
pave the way for potential preclinical and clinical trials
for the treatment, in particular treatment of T-69 patients.
So does this have any implication for other AML
subtypes? That's that's very interesting
as well. And this is actually has been
studied before because a hoax genes are overexpressed in so
many other subtypes. So in those subtypes is being
the role of XPO one involved in the regulation of these genes is
is being currently studying so far by other groups.
So it seems like XPO one by the interaction through other
factors may have a role in the upper regulation of these genes
in other subtypes with these things are also up regulated.
So the the particular use of XPO 1 inhibitors is being currently
studied for the treatment of other patients with the
respiration of XPO 1 of HOX genes like for example MPN 1
motivated patients or MLLA rearranged patients as well.
So what are the next steps for this?
Research. So definitely we need to expand
these research in other models before starting a clinical trial
and but there are still lots of questions from the molecular
perspective that are still open. So I really want to understand
how these two proteins interact through which domains.
And if apart from the genes that we looked into like Hoxins or
Foxy one, as I mentioned before, if there are other key leukemia
genes that are also regulated by the interaction of these two
proteins, the kinetic protein and XPO one that may have a role
in leukemia even if they've not been related to a metopoiesis or
leukemia before. To identify other mechanisms
that that can can explain this malignant transformation and how
this subtype is is very aggressive as well as the
interaction with free 3 ITD mutation.
Because it's quite interesting that these patients with the D69
translocation also acquired the Fleet 3 ATD mutation in more
than 70% of the cases. So it will be very interesting
to see if there is any relationship between the fusion
protein Fleet 3 ATD. So if they if they have a role
in inside cells and if X PO1 is somehow involved in this.
So because if that's the case, if X PO1 is somehow related with
Fleet 3 ATD, then we kind of expand the use of XP-1
inhibitors for other sometimes like flea 380 mutated patients,
which are really, really common. So this project was funded
thanks to a grant from EHA. Can you reflect on how this
grant has helped your career? Yeah, I mean, I'm really, really
grateful to the EHA because I think really this, this getting
this grant was key turning point on, on my, on my career.
So it helped me so much to my independence.
It I, I was, I was appointed as a Lecter when I got this, this
fellowship because it was my first funding as a, as API.
So then I could establish my own research group at the Bar's
Cancer Institute in London. And after that I got more
funding and I gave me the opportunity also to complete
this super exciting project that we recently published.
So it was a really beautiful story.
Now I moved my group to, to Madrid today, but keeping my, my
relationship with, with London. So, but everything I started
with the EHA research grant. So I'm really, really grateful.
So what would you tell young investigators that they're
thinking of applying for a Young EHA grant?
Please do it. Do it because I mean it changed
completely my my career and I think it's a great opportunity,
but not just for the funding itself that obviously is is what
we need to move forward in our career for sure, but also for
the visibility. And there because it's it's the
prestigious of these grants is very well known in the community
of hematologists and researchers in hematology.
So that's one of the key things as well because it gives you
visibility. So then you get much more
opportunities around like tearing sessions, being
involved, giving talks and knowing all the scientists or
their hematologist. So it's like a fantastic
opportunity. So please do it there.
It's not only the the junior one that is the one that I got, but
there is there are more like the advanced and also lots of
opportunities for collaboration with among different groups.
Are you involved in other ways in AK now?
Yeah, I'm part of the mentoring program committee.
So he's a new program that is launching EATA this year.
So he's we are matching mentees and mentors and I hope it's
going to work right. Yeah, I'm, I'm part of this this
committee organizing, organizing this new initiative that I think
is going to be fantastic and hopefully it will continue for
many years. What is the best part of your
job? Well, but definitely like
knowing people doing research in in hematology.
So I think it's the part that I love the most, like seeing what
others do and collaborating with, with other people, with
the, with the prejudice was funded by, by, I'd say I had the
opportunity of supervising for the first time my own PhD as
student and seen how happy she was when, when the experiments
worked, when our hypothesis, the one that I wrote when I applied
for the EITA worked as well. And it was guiding the, the
continuation of the project. I think it was the most
rewarding thing that I ever, ever experienced.
So that confirmed that I what I want to do, like research,
training other people, like building my group and and see
how working together we can get somewhere.
And what is more difficult in your job?
In funding. Getting the fun.
So, yeah, yeah, definitely that's that's the most
challenging part for for every research.
I mean the future is in the collaborations, that's for sure.
So I think we can't be experts of everything.
So if we want to make research that change the way in which we
treat the patients, the way in which the patients are cured and
managed, we definitely need to work together with including
everything. No, like artificial intelligence
now by informaticians research and doing experiments hand on in
the lab and lots of people thinking, connecting and
talking, talking and doing brainstorming.
So that's, that's the future. So I think the funding will come
through all these ways as well that most of the founder bodies
are also seen that that's the the way in which we should be
working. Yeah.
For clinical trials or for anything that you have to test
now. So you will need a lot of.
Totally. Yeah, collaboration and
interactions. Exactly with industry as well.
So definitely that's the future. We can't forget the rare
subtypes of acute malial leukemia.
So because they, it matters, it's a really aggressive
disease, but there are some subtypes within the, the AML
that are even worse than others. And they, we, we, we can't
forget those. Because I was asked in lots of
interviews why focusing on a rare subtype within a rare
disease? Because I mean, fortunately, AML
is not really, really frequent, but it's super aggressive.
Let's focus on restart types as well because they matter.
They are, they are patients, they, it's people behind
suffering of this disease. So that's one thing that
collaborations are needed for make a science bigger and to get
impactful results, and that's it.
Well, thank you very much for being with us today, Doctor Leo
Machine, and thank you for all the audience to report listening
and stay tuned for more episodes.
Thank you very much for the mutation.