Latest / EHA Unplugged / EHA Junior Research Grant: Dr Ana Río-Machín’s Journey in AML Research and Collaborative Science

Transcript

EHA Junior Research Grant: Dr Ana Río-Machín’s Journey in AML Research and Collaborative Science · EHA Unplugged

• 0:00
  Please do it, do it because I mean, it changed completely my
• 0:04
  my career. And I think it's a great
• 0:05
  opportunity, but not just for the funding itself.
• 0:08
  That obviously is, is what we need to move forward in our
• 0:12
  career for sure, but also for the visibility.
• 0:15
  And because it's, it's, I mean the prestigious of these grants
• 0:19
  is very well known in the community of hematologist.
• 0:27
  Welcome to EHA Unplugged, the official podcast channels of the
• 0:30
  European Hematology Association. EHA.
• 0:33
  I am your host, Isabella Libera, and today we have the pleasure
• 0:38
  to have with us Doctor Anario Machin.
• 0:40
  Welcome. Thank you very much for having.
• 0:42
  Me So Doctor Anario Machin is HPI at the Hematology
• 0:47
  Experimental Lab, Tonoma de Madrid and she's also an
• 0:50
  honorary lecturer at the Center for Hemato Oncology at the Barts
• 0:54
  Cancer Institute in the Queens Mary University of London.
• 0:58
  Her research aims to improve the understanding and management of
• 1:02
  familial AML acute myeloid leukemia and focuses on
• 1:08
  exploring GEM line mutations in families with AML.
• 1:12
  Doctor Rheomachin's work has was supported by an EHA Junior
• 1:17
  research grant. Her results have been recently
• 1:20
  published and we will be discussing them today.
• 1:23
  So we will start by analyzing why she's studying family and
• 1:28
  AML, then why she has focused on a certain translocation and what
• 1:36
  the consequences of this translocation are and how they
• 1:41
  activate key leukemia genes. And finally, we will see how
• 1:46
  this is clinical relevant at the moment.
• 1:49
  So let's start by the basis, looking at the big picture, why
• 1:54
  work in familial AML? Thank you, Mami.
• 2:00
  There are two weeks groups of accumulated leukemia the
• 2:03
  sporadic cases, but we are always forgetting about the
• 2:06
  familial cases that are the ones where we are inherited A
• 2:10
  mutation that can cause the disease.
• 2:12
  So we this is this was recognized very recently by The
• 2:16
  Who classification of myeloid neoblasms.
• 2:19
  So before 2015 even if we knew that there were some aggregation
• 2:24
  in families and nothing was really done for the diagnostic
• 2:28
  of these of these families, we were investigating in new genes
• 2:33
  that could be like causing this predisposition to do acute my
• 2:37
  leukemia and other myeloid neoblasms.
• 2:40
  So we considered that it was really, really relevant to look
• 2:43
  into these families, identify the genetic cause of these of
• 2:46
  these, especially at the point of the transplantation.
• 2:49
  Because so far we know that the the cure of these patients is
• 2:53
  the, the, the transplantation. The best donor is normally a
• 2:57
  familiar or a relative of the of these patients.
• 3:00
  But if the patient, if the relative has also the, the, the
• 3:04
  jetline variant, the the recipient will develop the
• 3:08
  disease again. So this is what we call donor
• 3:11
  derived leukemia and is really aggressive.
• 3:14
  So we need to avoid that. So we need to understand the
• 3:17
  genetics behind familial cases. Then my work also focus on the
• 3:23
  sporadic disease like so I have like a 2 main lines of research
• 3:27
  of my research. One focus on familial cases, but
• 3:31
  the other is in a sporadic disease like for example this
• 3:34
  rare subtype that is the the patients with the the
• 3:37
  chromosomal translocation between chromosome 6 and
• 3:39
  chromosome 9. So this translocation between
• 3:42
  chromosome 6:00 and 9:00, you say this is sporadic, it's not.
• 3:46
  Familiar. It's not familiar.
• 3:49
  So this creates a fusion protein.
• 3:51
  What are the consequences of this fusion protein?
• 3:53
  What does it do? That was exactly what we wanted
• 3:56
  to to understand with this project because it is a
• 3:59
  recognized subtype is again in the myeloid classification by
• 4:04
  who? But so everybody knows that it
• 4:07
  exists is quite a frequent, but the consequences of and the
• 4:11
  function of this fusion gene, it was still unknown and the basics
• 4:16
  didn't have any any specific therapy for.
• 4:19
  So what we did know is like this.
• 4:21
  The transportation between chromosome chromosome 6 and
• 4:24
  chromosome 9 results in a fusion gene between the DECK gene and
• 4:30
  Nope 214 gene. So the consequence of this
• 4:33
  fusion gene is a chimeric protein, half of DECK and half
• 4:38
  of Nope 214. So that was known.
• 4:41
  But how these kinetic protein induces the development of acute
• 4:46
  myeloid leukemia was still unknown.
• 4:49
  And the patients, these patients with this translocation have a
• 4:52
  really poor prognosis, especially when this
• 4:54
  translocation occur at the same time with the fleet three IT DE
• 4:57
  mutation that is quite frequent. Normally more than 70% of these
• 5:01
  patients also appear these fleet 3 ITD mutation.
• 5:06
  So they the the prognosis of these patients is really poor.
• 5:08
  The age of the diagnosis of these patients is younger than
• 5:12
  the average for acute malaria leukemia or they normally have a
• 5:15
  really high rate of relapse so that because there is no
• 5:18
  actually so they respond, but then they relapse because the
• 5:21
  clone with the translocation is still there and it causes the
• 5:25
  relapse of the disease. So we really wanted to
• 5:27
  understand how this kinetic protein could induce leukemia
• 5:32
  and if there was something that we could target to kill these
• 5:35
  leukemic cells. So what are the targets of this
• 5:42
  fusion protein? So the main finding of our
• 5:47
  project and that we are really proud of is like we found that
• 5:51
  BEKNUP 214 acts as a transcription factor.
• 5:55
  So it binds to the regulatory region of key leukemia genes
• 5:58
  like HOX genes or FOXY one who's an induced and these induces the
• 6:04
  overexpression of these key leukemia target genes.
• 6:07
  So then what we know is the overexpression of FOXY one or
• 6:10
  HOX genes induces leukemia. So this is already known because
• 6:13
  they are genes overexpressed in other subtypes of leukemia.
• 6:17
  But what we identified was the what was causing this
• 6:21
  overexpression, That was the binding of Decknum 214 to the
• 6:24
  regulatory regions. So then understanding why these
• 6:28
  genes are inducing leukemia, it was quite well studied before
• 6:34
  because FOXY one for example, blocks differentiation.
• 6:37
  But this is one of the heats that normally occur to for to
• 6:42
  induce leukemia leukemia development.
• 6:45
  And also as well the over expression of hoax genes that
• 6:48
  are really, really well known targets and are over expressed
• 6:51
  in other subtitles like the ones with KMDT to a rearrangements.
• 6:56
  So the the novelty was identifying this new this new
• 7:00
  role for techno 214 over expressing, inducing the over
• 7:03
  expressing of these teams. And what it was more important
• 7:06
  it was the the group 214 in binds to this region with the
• 7:12
  help of XPO 1. And XPO 1 is a is a protein that
• 7:17
  binds to the group 214 and is required these binding for the
• 7:21
  over expression of hoax genes and FOXY one among other genes.
• 7:27
  And it was really interesting because we had a good
• 7:29
  representation of patients with A-69 translocation given that it
• 7:34
  was a very rare entity. And we compare, we compare the
• 7:39
  response of this space of this cell, the cells of these
• 7:41
  patients with the T-69 translocation with the response
• 7:44
  to for other AML subtypes. So we treat in all these cells
• 7:49
  with more than 527 compounds. And it was really interesting to
• 7:54
  find that on the top of the list.
• 7:56
  So the the compounds that were more specific and more selective
• 8:00
  for the T-69 patients were the XP-1 inhibitors.
• 8:03
  So there was a clear relationship between our
• 8:07
  finding, so identifying XPO one being super specific and
• 8:11
  efficient for the T-69 patients compared to other AML subtypes
• 8:17
  and the the fact that Techno 214 interacts with XPO 1.
• 8:22
  So then we went a step forward. So we found that Techno 214
• 8:28
  requires XPO 1 interaction to induce the best person of these
• 8:32
  genes that I mentioned before. And when we treat the patient
• 8:37
  cells with XP-1 inhibitors, this binding is lost.
• 8:41
  And this the expression of these key leukemia genes was reduced
• 8:45
  causing the the the the kill of the of these cells, leukemia
• 8:49
  cells. So in a in a way we identify a
• 8:53
  potential targeted therapy 46, nine patients so.
• 8:59
  That would be my question. Can you use this XPO 1
• 9:02
  inhibitors in patients? Is it known whether this is safe
• 9:07
  to use and? That's, that's a very
• 9:09
  interesting question because XP-1 inhibitors 11 cellinexor
• 9:13
  for example, is an XP-1 inhibitor approved for the
• 9:16
  treatment of multiple myeloma, which is great because it's
• 9:18
  approved already. So it will speed up the the the
• 9:22
  possibility of use of being used for acute minor leukemia
• 9:26
  treatment however is very toxic. So there are new versions of XPO
• 9:31
  1 inhibitors coming now and being studied in preclinical and
• 9:34
  clinical studies. So probably in the in the coming
• 9:38
  years, we will have more safe XPO 1 inhibitors that can be
• 9:42
  definitively be tested. So I believe our research will
• 9:47
  pave the way for potential preclinical and clinical trials
• 9:53
  for the treatment, in particular treatment of T-69 patients.
• 9:56
  So does this have any implication for other AML
• 10:01
  subtypes? That's that's very interesting
• 10:05
  as well. And this is actually has been
• 10:06
  studied before because a hoax genes are overexpressed in so
• 10:12
  many other subtypes. So in those subtypes is being
• 10:17
  the role of XPO one involved in the regulation of these genes is
• 10:22
  is being currently studying so far by other groups.
• 10:25
  So it seems like XPO one by the interaction through other
• 10:29
  factors may have a role in the upper regulation of these genes
• 10:32
  in other subtypes with these things are also up regulated.
• 10:36
  So the the particular use of XPO 1 inhibitors is being currently
• 10:42
  studied for the treatment of other patients with the
• 10:44
  respiration of XPO 1 of HOX genes like for example MPN 1
• 10:50
  motivated patients or MLLA rearranged patients as well.
• 10:55
  So what are the next steps for this?
• 10:56
  Research. So definitely we need to expand
• 10:58
  these research in other models before starting a clinical trial
• 11:03
  and but there are still lots of questions from the molecular
• 11:07
  perspective that are still open. So I really want to understand
• 11:11
  how these two proteins interact through which domains.
• 11:16
  And if apart from the genes that we looked into like Hoxins or
• 11:21
  Foxy one, as I mentioned before, if there are other key leukemia
• 11:25
  genes that are also regulated by the interaction of these two
• 11:28
  proteins, the kinetic protein and XPO one that may have a role
• 11:32
  in leukemia even if they've not been related to a metopoiesis or
• 11:36
  leukemia before. To identify other mechanisms
• 11:39
  that that can can explain this malignant transformation and how
• 11:44
  this subtype is is very aggressive as well as the
• 11:47
  interaction with free 3 ITD mutation.
• 11:50
  Because it's quite interesting that these patients with the D69
• 11:53
  translocation also acquired the Fleet 3 ATD mutation in more
• 11:58
  than 70% of the cases. So it will be very interesting
• 12:01
  to see if there is any relationship between the fusion
• 12:05
  protein Fleet 3 ATD. So if they if they have a role
• 12:09
  in inside cells and if X PO1 is somehow involved in this.
• 12:14
  So because if that's the case, if X PO1 is somehow related with
• 12:18
  Fleet 3 ATD, then we kind of expand the use of XP-1
• 12:22
  inhibitors for other sometimes like flea 380 mutated patients,
• 12:26
  which are really, really common. So this project was funded
• 12:31
  thanks to a grant from EHA. Can you reflect on how this
• 12:38
  grant has helped your career? Yeah, I mean, I'm really, really
• 12:42
  grateful to the EHA because I think really this, this getting
• 12:45
  this grant was key turning point on, on my, on my career.
• 12:51
  So it helped me so much to my independence.
• 12:53
  It I, I was, I was appointed as a Lecter when I got this, this
• 12:57
  fellowship because it was my first funding as a, as API.
• 13:02
  So then I could establish my own research group at the Bar's
• 13:05
  Cancer Institute in London. And after that I got more
• 13:09
  funding and I gave me the opportunity also to complete
• 13:12
  this super exciting project that we recently published.
• 13:16
  So it was a really beautiful story.
• 13:18
  Now I moved my group to, to Madrid today, but keeping my, my
• 13:24
  relationship with, with London. So, but everything I started
• 13:27
  with the EHA research grant. So I'm really, really grateful.
• 13:33
  So what would you tell young investigators that they're
• 13:37
  thinking of applying for a Young EHA grant?
• 13:41
  Please do it. Do it because I mean it changed
• 13:44
  completely my my career and I think it's a great opportunity,
• 13:47
  but not just for the funding itself that obviously is is what
• 13:51
  we need to move forward in our career for sure, but also for
• 13:56
  the visibility. And there because it's it's the
• 13:57
  prestigious of these grants is very well known in the community
• 14:01
  of hematologists and researchers in hematology.
• 14:05
  So that's one of the key things as well because it gives you
• 14:09
  visibility. So then you get much more
• 14:13
  opportunities around like tearing sessions, being
• 14:16
  involved, giving talks and knowing all the scientists or
• 14:20
  their hematologist. So it's like a fantastic
• 14:22
  opportunity. So please do it there.
• 14:25
  It's not only the the junior one that is the one that I got, but
• 14:28
  there is there are more like the advanced and also lots of
• 14:32
  opportunities for collaboration with among different groups.
• 14:38
  Are you involved in other ways in AK now?
• 14:41
  Yeah, I'm part of the mentoring program committee.
• 14:44
  So he's a new program that is launching EATA this year.
• 14:49
  So he's we are matching mentees and mentors and I hope it's
• 14:54
  going to work right. Yeah, I'm, I'm part of this this
• 14:56
  committee organizing, organizing this new initiative that I think
• 15:01
  is going to be fantastic and hopefully it will continue for
• 15:04
  many years. What is the best part of your
• 15:08
  job? Well, but definitely like
• 15:14
  knowing people doing research in in hematology.
• 15:18
  So I think it's the part that I love the most, like seeing what
• 15:22
  others do and collaborating with, with other people, with
• 15:26
  the, with the prejudice was funded by, by, I'd say I had the
• 15:30
  opportunity of supervising for the first time my own PhD as
• 15:34
  student and seen how happy she was when, when the experiments
• 15:40
  worked, when our hypothesis, the one that I wrote when I applied
• 15:43
  for the EITA worked as well. And it was guiding the, the
• 15:48
  continuation of the project. I think it was the most
• 15:51
  rewarding thing that I ever, ever experienced.
• 15:55
  So that confirmed that I what I want to do, like research,
• 15:58
  training other people, like building my group and and see
• 16:02
  how working together we can get somewhere.
• 16:06
  And what is more difficult in your job?
• 16:08
  In funding. Getting the fun.
• 16:11
  So, yeah, yeah, definitely that's that's the most
• 16:13
  challenging part for for every research.
• 16:17
  I mean the future is in the collaborations, that's for sure.
• 16:19
  So I think we can't be experts of everything.
• 16:24
  So if we want to make research that change the way in which we
• 16:28
  treat the patients, the way in which the patients are cured and
• 16:34
  managed, we definitely need to work together with including
• 16:39
  everything. No, like artificial intelligence
• 16:41
  now by informaticians research and doing experiments hand on in
• 16:47
  the lab and lots of people thinking, connecting and
• 16:51
  talking, talking and doing brainstorming.
• 16:54
  So that's, that's the future. So I think the funding will come
• 16:56
  through all these ways as well that most of the founder bodies
• 16:59
  are also seen that that's the the way in which we should be
• 17:03
  working. Yeah.
• 17:06
  For clinical trials or for anything that you have to test
• 17:09
  now. So you will need a lot of.
• 17:11
  Totally. Yeah, collaboration and
• 17:13
  interactions. Exactly with industry as well.
• 17:15
  So definitely that's the future. We can't forget the rare
• 17:19
  subtypes of acute malial leukemia.
• 17:21
  So because they, it matters, it's a really aggressive
• 17:24
  disease, but there are some subtypes within the, the AML
• 17:28
  that are even worse than others. And they, we, we, we can't
• 17:33
  forget those. Because I was asked in lots of
• 17:36
  interviews why focusing on a rare subtype within a rare
• 17:39
  disease? Because I mean, fortunately, AML
• 17:42
  is not really, really frequent, but it's super aggressive.
• 17:46
  Let's focus on restart types as well because they matter.
• 17:49
  They are, they are patients, they, it's people behind
• 17:52
  suffering of this disease. So that's one thing that
• 17:56
  collaborations are needed for make a science bigger and to get
• 18:01
  impactful results, and that's it.
• 18:06
  Well, thank you very much for being with us today, Doctor Leo
• 18:11
  Machine, and thank you for all the audience to report listening
• 18:15
  and stay tuned for more episodes.
• 18:18
  Thank you very much for the mutation.