What Does Differentiation Mean?

Immature blood forming cells start out similar in appearance, but they differentiate as they develop and mature into specific types of blood cells..


Differentiation refers to the series steps that a cell goes through to become mature. As a cell develops, it begins to show its own purpose and role in the human body, a process known as differentiation.

Cells may be immature because they are rapidly growing from a new start, such as in the development of a baby in the womb; however immature cells that lack differentiation also occur normally in adults -- for instance, in tissues and organs that constantly replace old cells with new ones, such as the bone marrow.

Fully differentiated cells are the ones we learn about in basic biology: red blood cells, brain cells or neurons or muscle cells, for instance. Differentiation is the process that shapes the immature cell’s destiny, determines the cell’s distinct role and results in specific characteristics tailored to the adult cell’s purpose. A skin cell is unlike a blood cell, for example. A mature, well-differentiated cell usually has a very specific role to play, with characteristics typical of the organ or tissue where it lives.

Differentiation in Cancer

In cancer, the process of differentiation may not occur normally. Cancer cells may be stuck in one phase of differentiation, may be less developed and may not function as well as the surrounding, healthy cells. In fact, sometimes these cells are so poorly differentiated that, under a microscope, they don’t even look like the cells that they developed from.

Pathologists are doctors who are trained to analyze cells and tissues, such as those submitted in biopsy specimens, to make a determination about disease. It used to be that pathologists relied heavily on what’s called morphology -- how the cells looked under the microscope: the size, shape or richness of color when special dyes and stains were applied.

This is still done, and yields important information about differentiation, but now there are other tests that are used as well. These tests can identify specific molecules on the outside of the cells that can sometimes be used to tell how well differentiated a cell is.

Differentiation in Blood Cancers

One of the reasons there are so many different kinds of lymphomas is that immune cells have many stages of development, differentiation and maturation. If you ever studied the development of blood cells, or hematopoiesis, you know that it’s not a simple thing -- there are multiple stages and different types of immature cells.

In the case of blood cancers such as leukemia or lymphoma, the cancerous white blood cells or lymphocytes range in how “well differentiated” they are. When cancer occurs, it often “locks” the cell -- and all of its cancerous offspring -- into the stage of development at which the cancer began.

Poorly differentiated cells may be similar in appearance to the original cells from which they developed, but they may not be able to do all of the jobs expected of healthy immune cells.

Cells that are poorly differentiated are less mature, more likely to grow fast, and also generally more susceptible to chemotherapy.

Well differentiated cells closely resemble mature cells and so they tend to divide and grow more slowly. Malignant cells that are well differentiated, like their normal counterparts, tend to grow slowly.

In some cases, information about differentiation can influence the prognosis and inform the treatment decision. In general, “well differentiated” translates to a lower grade cancer, while “poorly differentiated” translates to a higher-grade malignancy.

Differentiation and Blood Cancer Classification

Multiple classification systems have been used for blood cancers over the years.

The current classification system, the 2008 World Health Organization (WHO) classification, takes a several different factors into account in order to determine the type of malignancy, and differentiation is one of these factors.

When possible, these malignancies are classified by their "lineage" into:

Differentiation within each lineage is also important. For example, lymphomas are cancers of the lymphocytes, which fall in the lymphoid neoplasm lineage. There are B lymphocytes and T lymphocytes. Let’s say you know your cancer is of the B lymphocyte lineage, or a B-cell lymphoma.

You can then have mature B cell lymphomas, which correlate to normal stages of B cell development and maturation. You can also have precursor B lymphoblastic leukemia/lymphomas -- these are cancers of immature cells that are committed to become members of the B-cell family.

Differentiation and Blood Cancer Treatment

A poorly differentiated lymphoma may be growing fast and more susceptible to chemotherapy that targets rapidly dividing cells.

Another example of differentiation that can be used to a patient's advantage occurs in acute promyelocytic leukemia, or APL. This malignancy is different from other types of AML in important ways. One of them is that, when APL cells are destroyed with chemotherapy, they release proteins that can cause the body’s blood-clotting mechanisms to go out-of-control, which can be deadly.

Scientists discovered that APL cells could be coaxed to transform into mature myeloid cells with certain drugs. Since this coaxing is actually differentiation, these drugs are called differentiation agents. Since the immature blasts don’t die with this kind of therapy, the harmful protein stays inside the cells, and the clotting process doesn’t get out of control.

Updated February 2016, TI.


Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009; 114:937.

American Cancer Society. Other drugs for acute myeloid leukemia. Accessed February 2016.

Gribbon, J., Loescher, L. Biology of Cancer in Yarbro, C., Frogge, M., Goodman, M., Groenwald, S. (2000) Cancer Nursing: Principles and Practice 5th ed Jones and Bartlett: Sudbury, MA. pp. 17- 35.

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