LBA-1 Driver Mutation Acquisition in Utero and Childhood Followed By Lifelong Clonal Evolution Underlie Myeloproliferative Neoplasms.
When do mutations in MPN start? Can we do genetic archeology?
Great study by @jyoti_nangalia
https://ash.confex.com/ash/2020/webprogram/Paper143813.html
#ASH2020 #ASH20RF #mmsm 1/x
I have always wondered about this in myeloma (MM). We now know that all MM patients have the preceding stage of MGUS. Studies were done in the US Army with stored blood samples (thousands) found *ALL* patients with MM had prior MGUS.
2/x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689043/
A monoclonal gammopathy precedes multiple myeloma in most patients

Preexisting plasma cell disorders, monoclonal gammopathy of undetermined significance, or smoldering myeloma are present in at least one-third of multiple myeloma patients. However, the proportion of...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689043/
So if all MM patients had preexisting MGUS, for how long has the MGUS existed? Mathematical modeling predicts decades. In this paper from @MayoClinic >10 yrs.
@VincentRK
3/x https://www.mayoclinicproceedings.org/article/S0025-6196(12)00634-9/abstract
Incidence of Monoclonal Gammopathy of Undetermined Significance and Estimation of Duration Before...

To determine the incidence of monoclonal gammopathy of undetermined significance (MGUS) in the general population and to estimate the duration of occult MGUS before first diagnosis.

https://www.mayoclinicproceedings.org/article/S0025-6196(12)00634-9/abstract
How many people have clonal plasma cells like a pre-MGUS (micro, mini, nano-MGUS!)? It is likely a lot. I'm going to go out on a limb that perhaps a majority of people do. I hear rumors that with mass spec many more MGUS detected.
4/x
This leads us to the hypothesis- if childhood/early adulthood is when we have most de novo immune challenges, by probability alone, one could say this is the most like time B cells acquire translocations and mutations? Hang on -part of a healthy childhood includes mutations!
5/x
As reminder myeloma can be broadly divided into those with translocations (~50%) and hyperdiploid.
@Leif_Bergsagel showed IgH translocations occur in late B cells at the time of class switching (i.e., switching from IgM to IgG in our immune response)
6/x
https://www.pnas.org/content/93/24/13931.long
The cartoon below is an oversimplification but MM is different by these two genetic subgroups with a bias for the elderly being more hyperdiploid, IgG kappa, males and with more bone disease. IgA lambda a bit more in high risk.
7/x
#mmsm
So it stands to reason that as we are exposed to more novel viruses, bacteria, etc. early in life there are more chances (numerically) for a translocation. Perhaps babies are better at repairing dsDNA breaks? So here is a point where it gets interesting for myeloma...
8/x
Some translocations (t(4;14) and MAF) and deletions (17p13) have been defined as a way to identify high risk. In this key paper from Dr. F. Ross we see hyperdiploidy (associated with a better outcome) more common in the elderly and vice versa for translocations.
9/x
I have always wondered if high-risk MM presents at an earlier age because it progresses earlier? Even a minor change in the risk of progression (slope in blue) can mean an earlier progression over many years.
10/x
It is also true that bone disease is less common in HR MM. Maybe there is a more rapid progression, less time to erode, alas a lower incidence of bone disease?
11/x
We did a study using very old fashioned karyotypes to determine the order of acquisition of genomic abnormalities. We found clear evidence of the primacy of trisomies and IgH translocations.
(Sad this paper is not very popular)
12/x
https://pubmed.ncbi.nlm.nih.gov/23856591/ 
And this seminal paper shows that like in MPD you can use mutations a carbon14 in myeloma and predict mutations start early in life! So the prediction is MM starts in childhood. Please read this beautiful paper!
@DrOlaLandgren @EHRustad
13/x
https://www.nature.com/articles/s41467-020-15740-9
So in short, MM started decades ago at diagnosis. Not recently.

I am on a mission to prove the existence of clonal PC in the young!
14/x
FIN
*** For curation purposes, I also placed images from the beautiful MPN presentation below.
Common questions from patients. They grew single-cell colonies and did WGS. They drew phylogenetic colonies
Common questions from patients. They grew single-cell colonies and did WGS. They drew phylogenetic colonies
Common questions from patients. They grew single-cell colonies and did WGS. They drew phylogenetic colonies
Common questions from patients. They grew single-cell colonies and did WGS. They drew phylogenetic colonies
Common questions from patients. They grew single-cell colonies and did WGS. They drew phylogenetic colonies
They convert relative timing to actual timing. They can trace back the inititaion to in utero. In some cases decades before diagnosis.m
They convert relative timing to actual timing. They can trace back the inititaion to in utero. In some cases decades before diagnosis.m
They convert relative timing to actual timing. They can trace back the inititaion to in utero. In some cases decades before diagnosis.m
They convert relative timing to actual timing. They can trace back the inititaion to in utero. In some cases decades before diagnosis.m
They convert relative timing to actual timing. They can trace back the inititaion to in utero. In some cases decades before diagnosis.m
Long history
Long history
Long history
Long history
Long history
The growth rate of clones varies per year.
The growth rate of clones varies per year.
The growth rate of clones varies per year.
The growth rate of clones varies per year.
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