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- [00:02]
A
Welcome to the American Society of Hematology conversations with Blood authors. This blood podcast episode is hosted by Dr. Laurie Sen. She discusses CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias with Dr. Vijay Sankaran and the companion article, MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia with Dr. Rude Delwell. Dr. Sen also discusses prognostic value of pre maintenance FDG PET CT response in patients with newly diagnosed myeloma from the Cassiopeia trial with Dr. Francois Kreber Bodeur.
- [00:48]
B
Hi, I'm Laurie Sen, podcast editor at Blood and I'm joined today by doctors Vijay Sankaran from Boston Children's Hospital and Rude Delwell from Erasmus Cancer Center, Netherlands. They're the senior authors of two important complementary articles in blood that demonstrate how CBP alpha repression by MECOM leads to differentiation block, thereby driving aggressive leukemias. Thank you both for joining us today. Dr. Sankaran, can you start by giving us some background on this pathway and the relevance that it may have in acute leukemias?
- [01:29]
C
Absolutely. We've known for a number of years that there are certain types of forms of acute myeloid leukemia driven by the MECOM gene that have a particularly poor prognosis. And this was initially noted about 10 years ago by Rudelwell's group and other groups that had identified a translocation that greatly upregulates this MECOM gene and causes these very stem cell like leukemias. And I mention that because since that initial observation, we've known that these leukemias have a poor prognosis. And yet why that is and what ME COM is doing to drive these very aggressive leukemias has remained largely unknown. And so that really, I think set the the background for what we were attempting to do and what Rud's group was attempting to do was just really to try to understand at a mechanistic level how is MECOM driving the programs that are ultimately leading to this aggressive nature of these leukemias. And we were rather surprised because our initial hypothesis had actually been that MECOM might be activating some genes, suppressing some genes, and doing a variety of different things in leukemias. But as we started to look, what we noticed was that MECOM actually seemed to be critical to primarily repress genes. And one tool that we had developed, and there was a similar kind of tool that Ruth's lab had developed, was actually to acutely get rid of MECOM in these MECOM driven leukemias by using genetic engineering to introduce what's called a degron tag. So we could essentially, by introducing a small molecule, selectively get rid of mecom. And that allowed us to examine across a couple of different cell types, how that acute degradation affected gene expression. And it turned out that very acutely, the majority of genes that were changing were genes that were upregulated. And then we started to wonder, well, is one of those particular targets absolutely essential for the survival of these leukemias? And it turned out that as we started to look further and further at this and do different functional genomic approaches, particularly looking at either repressing genes after removing ME com or, or in the presence of ME com, activating some genes, we found that there was a single target that actually appeared to be absolutely necessary, which was bound by mecom. And this was a region that was regulating the expression of this other key transcription factor, CBP Alpha, that you'd mentioned before. And so really that seemed to be necessary and sufficient to enable the differentiation of these leukemia. So activating CBP alpha expression caused these leukemias to take on features of differentiating cells. It caused the leukemias to lose many of their stem cell features. And this seemed to be the primary target, at least in these leukemia cell lines, that was necessary for these cell lines to continue and progress.
- [04:57]
B
Fascinating. Dr. Delwell used a slightly different approach. Can you tell us what your research showed?
- [05:04]
D
Yeah, thank you for this question. In a way, I think Vijay really explained very well that we both used very comparable approaches, although a little bit different. We also used an approach where we degraded EVR1 or Mecom, I should say. And the old, the old name for me was EVR1. So some people may listen and realize, never heard of Mecom and when you hear EVR1, they know what we are talking about. And we found exactly the same thing. We also found that if you degrade me very quickly, and then we then did another approach to really measure the immediate genes that would be turned on or off when you degrade the, you know, mecom. Then we found indeed also that this CBP alpha gene was very rapidly upregulated. That sense. We found exactly the same thing, which I really like, it's the third time in my career, honestly, that we do a study and there's another group really sort of validating and they should say the other one, the opposite. We did an experiment and they were validated, but really validated each other's data, really showing. I think that what we found is absolutely essential. And it's true, right? We both found it.
- [06:24]
B
Well, it Certainly is. It's very validating and perfect timing, I would say so. In their commentary, Nicola Wilson and Berthold Gottngen from the University of Cambridge highlight the simplicity of this mechanism, that it essentially constitutes a regulatory switch that can move leukemic cells out of malignant prolife. So, Dr. Sankaran, what do you think the therapeutic potential of these implications are?
- [06:52]
C
I think it's a really terrific question from two aspects. At a mechanistic level, I think it really suggests that there's to some extent some simplicity. You know, there's a very simple regulatory circuit involved in preventing these leukemias from differentiating, in maintaining their stem cell like features. And really it's that by just switching on CBP alpha, you can totally cause the cells to differentiate, you can prevent the stem cell features. I think at a mechanistic level, it really suggests that we're learning something very simple that could have enormous therapeutic implications by that. We know for some leukemias, particularly for acute promyelocytic leukemia, that the real advances in treating that leukemia, where it's gone from really being a very deadly aggressive leukemia to being one that's highly treatable, came about largely from the discovery and development of differentiation therapies. In a similar way, we know that treating these inversion 3, or what are now referred to as AMLs, with MECOM rearrangements is often challenging with conventional AML directed chemotherapy or even allogeneic transplantation in many patients. And so our hope is by better understanding this mechanism, we have the opportunity now to think about how we could push differentiation of these cells. And perhaps that's a valuable target to go after as we think about trying to treat these leukemias.
- [08:30]
B
The other thing that the commentary authors mentioned were that despite its simplicity, when you start to think about therapeutic implications and consider long term suppression of these pathways, that it might actually induce resistance mechanisms. Dr. Delwell, do you have any thoughts on this?
- [08:48]
D
What I really think that we have to do here. So this type of leukemia is resistant by definition currently with current therapies. Right. I think I'm not a doctor, I'm not a clinician, but what I know of these leukemia is that I think, and Dr. Sankaran can maybe comment on that, but I think 75% of those leukemias don't even get into remission. They're totally insensitive to current chemotherapy in general. So I think what really is important here is that we have to do everything we can. And I think Dr. Sankron really explained it very well and made the right comparison with APL where we know, and I think here too is that these tumor cells are totally dependent on the oncogene. They are addicted to this oncogene. And like in APL there, where the oncogene, where you eliminate the oncogene, then those tumor cells, you really hit the stem cells there and they differentiate. I think if we are able to do the same thing here, target the oncogene either by either, you know, interfering with transcription that the gene cannot be generated anymore, or by interfering with its presence, by eliminating it, or by interfering its function. And that's also another part of both of our studies that we know that if you have one mecon forms a complex with another protein and if you're able to interfere, and I think we are able to do that and I think one day we're going to get, you know, come with small molecules like menin or other inhibitors that we have nowadays. If we're able to interfere with the function between when we can interfere wecon and its binding partners, I think we may at some point come to a situation that we have now with APL, that we now have with MLL rearrange or KTM2 a rearranged leukemias, also these leukemias, one day we will be able to, I really believe in that, be able to really target that bad guy and come with new treatments.
- [10:58]
B
Well, one final question, Dr. Sankaran. Where do you think the field should take these results?
- [11:04]
C
I think that there's a lot that we hope will follow these studies. And I think one area that I think is an immediate area to pursue is to better understand some of these mechanisms at a fundamental level what is driving this and hopefully that can also motivate people to think about as rude was mentioning how we can interfere with this pathway using small molecules or other targeted approaches. And so I think that that's going to be particularly important in these leukemias because we know they're incredibly aggressive. And I would say even beyond just the cases of AML with MECOM rearrangement, we know in some of the recent gene therapy trials such as the adrenal leukodystrophy trial that was led by Christy Duncan and Dave Williams, that there many patients insertions that actually activated me calm. And so once again in many of those cases of gene therapy related leukemias, we're seeing this gene once again get activated. So understanding these pathways I think will have broad implications. But I do think, and I do hope that for many of these patients we'll be able to offer better treatments. There's a really moving and touching essay that Tatiana Schlossberg, the granddaughter of John F. Kennedy Jr. Had written. And that I think really exemplifies how patients with this kind of leukemia and she has AML with MECOM rearrangement and described how she had been through two allogeneic transplants, received CAR T cell therapy and yet her leukemia has returned and how it's impacting her and as she's, you know, looking towards not necessarily achieving a cure. And I think that really many, many patients face a circumstance. And so our hope is really by better understanding this we can and offer more options for patients in the future.
- [12:50]
B
Thank you. I think you really highlight that important unmet need and why research like this is so critical. Well, I hope you've enjoyed the conversation today with doctors Vijay Sankaran and Rude Delwell. Their important studies lay the groundwork for the potential development of novel differentiation strategies in high risk AML. Both of these articles are now available on bloodjournal.org I'm also joined today by Dr. Francoise Crber Bouderet from Nantes University in France. She's the lead author of a new Blood Journal article entitled Prognostic Value of Pre Maintenance FDG PET CT response in patients with Newly diagnosed Myeloma from the Cassiopeia trial. Thanks for joining us today. Perhaps you can start by giving us some background on the design of the Cassiopeia trial and its initial findings.
- [13:48]
E
So Cassiopet study is ancillary study of The Cassiopeia Phase 3 Prospective Clinical Trial by Professor Philippe Moreau and The Cassiopeia Phase 3 clinical trial assess the DARA anti CD38 monoclonal antibody associated with chemotherapy fertilized therapy of newly diagnosed multiple myeloma patients eligible for transplantations. And the Cassiopet study is ancillary study assessing the prognostic value of the FDG PET at baseline before the therapy as well as prognostic value at premanence and the premanence assessment was the primary objective of the Casio PET study.
- [14:34]
B
So for this Casio PET study, which is the primary topic of the paper, can you tell us why this question was of interest to you and the basic design of this companion study?
- [14:46]
E
Yes, of course we knew that already the prognostic value of FDG PET before therapy or at different time of the assessment of patients with multiple myeloma. But it was a casioped study, was the first time assessing the prognostic value in patients receiving dara and it is important the PET response and The PET abnormality after the therapy is potentially a prognostic biomarker and it's important to assess the prognostic biomarker this prognostic biomarker in patients treated with DARA because the kasiopoeia study allows the approval of DARA in new Lean diagnosed multiple myeloma patients.
- [15:29]
B
And what were the findings of your study?
- [15:32]
E
The study demonstrated the prognostic value on pfs as well as OS of a complete response based on FDG PET and a complete response defined using the standardization of the PET assessment already performed and published in 2022 with the team of Bologna in Italy and the team in Nantes in France. And then we used in the Casio PET study a standardization for the assessment of FDG pet and we demonstrate that the complete response metabolic complete response at premanence at prognostic value on PFS and on os and moreover we demonstrate as well the complementarity between FDG PET response and the MRD assessed by flow cytometry in the bone marrow.
- [16:28]
B
What do you think the clinical implications of these findings should be?
- [16:32]
E
So clinical application is very important because this study demonstrates that it is important to combine FDG PET with bone marrow MRD at premanence to assess the efficacy of the therapy. And in particular, because we know that multiple myeloma is a very heterogeneous disease, it is important to have the assessment inside and outside the bone marrow. And with FDG PET you have whole body cartography of the disease and you have the assessment of the bone marrow as well as extramedullary disease.
- [17:09]
B
In his commentary, Jens Hillengas from Roswell Park Comprehensive Cancer center raised the question about whether or not FDG PET is going to going to be the best assessment tool for myeloma. Moving forward, should we be considering other tracers or maybe functional mri? Can you comment on this?
- [17:29]
E
Of course. I am nuclear physician so I have expertise in FDG PET and not in the other imaging modalities. And we know potentially that mri, especially with advanced sequences and diffusion can improve the sensibility of the detection of the mrdf, so the therapy and also in particular for the diffuse bone Mar1 filtrations. However, we have a lot of prospective study showing the prognostic value of FDG PET and I think that there is important demonstration of the prognostic value of FDG PET and moreover there is demonstration of the complementarity between MRD assessed in the bone marrow and FDG pet. So probably it's possible to improve the sensitivity of the imaging using advanced sequences by MRI in particular, but we have to demonstrate this by prospective study the prognostic value of MRI as we already performed for FDG pet.
- [18:35]
B
As a final question, what other questions do you think we should be asking in the next set of clinical trials?
- [18:42]
E
We should in the new clinical trial assessment of the prognostic value of FDG PET of maybe MRI using advanced sequences combined with MRD in the bone marrow at different time of the evaluation.
- [18:59]
B
Excellent. I hope you've enjoyed the conversation today with Dr. Francoise Crber Baudure. She's been discussing her newly published article Prognostic Value of Premaintenance FDG PET CT Response in patients with Newly Diagnosed Myeloma from the Cassiopeia trial. This study highlights the prognostic significance of pre maintenance PET scanning in the era of quadruplet therapy which may guide treatment decisions in the future. This article is now available on bloodjournal.org.
- [19:37]
A
Thank you for listening to this blood podcast of conversations with blood authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.