Do you read about myeloma chromosomal translocations and your eyes just glaze over? Does it make little to no sense? You are not alone. Many of us struggle to understand chromosomal translocations. Technically, translocations are when chromosomes swap places, for example in a 4;14 translocation, the 4 and 14 chromosomes exchange spots on the DNA strand. Let's not focus on all that swapping though because it tends to make folks eyes glaze over. Instead, my hope is by the end of this article you will understand a little more about why translocations are important to the myeloma cell, how they impact MM aggressiveness and how they sustain the survival of the myeloma cell.
One of the first things that helps in understanding translocations is knowing how they impact cell cycle progression. What is cell cycle progression? Please look at the image posted to the left. It depicts what every cell (normal cells also) does to grow and sustain itself, each step along the way requires different enzymes and proteins for the cell to finish the cycle. What this means is the cell cycle is essential to sustain the survival of the cancer cell. Such that a big goal of the cancer cells is to control (hijack) the cell cycle progression. The primary way myeloma cells do this is via chromosomal translocations. Before we get to those, however lets look more closely at the cell cycle and it's importance to the cancer cell.
There are some key features/phases of the cycle, pictured above, which are color coded. First is the GREEN (G1) phase this is where the cell begins to grow, next is the ORANGE (S) phase where synthesis of DNA occur and then there is the PURPLE/BLUE (G2) phase where the cell grows more & prepares to divide. Third, there is the TURQUOISE (M) phase that results in 2 cells (replication), the cycle can be halted or begin again which is called G0. So, G means growth, S is for synthesis and G0 is for growth halted. Each of these phases of the cell are impacted by enzymes & proteins that can drive growth, replication & synthesis of the cell. Hopefully, this is creating an aha! moment. No wonder the cancer wants to gain control of this cell cycle progression. That's right! Controlling the cell cycle progression is important for replication, synthesis and growth of the cancer cell.
Cyclin D family & Cyclin Dependent Kinases (CDK)
This next image on the right shows where different enzymes regulate the G1,G2, GO and S phases of cell growth. With this image you can see one of the first and universal events in progression of MM is the dysregulation of the Cyclin D (CycD) family and the cyclin dependent kinases (CDK) which are key proteins that regulate the G1 phase.
What do the Cyclin D (CycD) family proteins & CDK enzymes do? Cyclin D & the CDK enzymes regulate the transition from the G1/S phase (i.e. proliferation). This means that when any of them are up regulated the cell is growing and driving towards synthesis (replication) constantly. It's like having the accelerator on cruise control on the highway.
Looking at the visual you can focus in on the phase where CDK2 is and see it drives synthesis and that CDK6 drives growth phase for replication. When both are dysregulated, proliferation goes into warp speed. CDK1 drives replication and CD1 pairs with CDK4 to drive proliferation. Recall the cyclins are a family and are numbered (i.e CD1-6)
Ok, now we are ready to move onto translocations. What are the specific translocations that alter, dysregulate and control the proteins in the cell cycle progression?
- t (11;14) seen in ~ 17% of cases, up regulates Cyclin D1
- t (6:14) seen in 2% of cases. Up regulates Cyclin D3
- t(14;16) occurs in 5-10% of cases. Upregulates c-MAF gene which targets Cyclin D2 (inhibits cell death/apoptosis) & integrin B7 (promotes adhesion to bone marrow)
- t(4:14) occurs in 10-15% of cases. Dysregulates the genes MMSET (increases proliferation) & FGR3 (inhibits DNA repair & apoptosis)
- t(14;20) occurs in 2% of cases. Up regulates MAFB which targets Cyclin D2.
All of these translocations occur on the myeloma cell chromosomes. These same chromosomal translocations are also used to determine risk.
Standard risk: t (6:14) and t (11:14)
Intermediate risk: t (4;14)
High risk: t (14;16) t(14;20)
I hope that this has given you a new way of looking at chromosomal translocations and perhaps understanding how they help to determine how aggressive the myeloma is based on the molecular biology. Yes, translocations are what they are talking about when the term "molecular biology" is included. Don't be put off by unfamiliar terms. Now, you too know what "molecular biology" is when they refer to it.
A future post will be coming soon on how different therapies can target the enzymes and proteins to help us defeat the control the translocations give to sustain the cancer cell.