Do all leukemias arise from hematopoietic stem cells?

Q. I have a quick question on the cell of origin in leukemia. In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? I think I remember from our pathology class that leukemia can also involve cells downstream of hematopoietic stem cells.

A. You’re absolutely right! And I’m so happy you caught that error, because that means you really understood the heme malignancies in our pathology class 🙂

Just to back up a bit: all leukemias arise from hematopoietic cells (either myeloid or lymphoid cells). But not all leukemias arise in hematopoietic stem cells.

Some leukemias arise in stem cells.

All of the chronic myeloproliferative disorders, for example, originate in stem cells. As a result, when you look in the blood and bone marrow, you see a proliferation of all different kinds of myeloid cells (red cells, neutrophils, and megakaryocytes) at all stages of maturation (neutrophils, myelocytes, metamyelocytes, etc.). In most of the chronic myeloproliferative disorders, a particular myeloid cell line dominates (in chronic myeloid leukemia (CML), for example, most of the malignant cells are neutrophils and precursors) – but because of the stem cell origin, there are other malignant myeloid cells present as well.

Here’s a cool thing. You’d think that the stem cell of origin in these chronic myeloproliferative disorders would be a myeloid stem cell, right? I mean, these disorders are composed of all kinds of myeloid cells – so the origin should be a myeloid stem cell. It turns out that the stem cell involved is actually a very young stem cell – it hasn’t even decided whether it wants to be myeloid or lymphoid! We know this because the characteristic genetic abnormality (for example, the Philadelphia chromosome in CML) is also present in lymphocytes. That explains why when CML evolves into blast crisis, the blasts may be either myeloid or lymphoid

Other leukemias arise in non-stem cells that belong to a specific cell lineage.

Acute promonocytic leukemia, for example, originates in a promonocyte (a stage of development between monoblast and monocyte). This means that when you look at the blood and bone marrow, you see mostly promonocytes (the cells in the image above with the lovely tissue-paper-like nuclei). Cells of other myeloid cell lineages (like red cells or neutrophils) are not present. These types of leukemias are a lot more straightforward.

Heme mistakes like this are common!

This kind of mis-statement (“all leukemias arise from stem cells”) happens a lot when people talk about hematopoietic diseases. Even the names of diseases are often stated incorrectly (e.g., “acute lymphoid leukemia” or “acute lymphocytic leukemia” instead of “acute lymphoblastic leukemia”). Heme is an area that many people shy away from, for some reason. I love it and find it really straightforward, but depending on how it’s taught, it can seem really confusing.

If you’re struggling with heme, there are tons of heme-related posts here on Pathology Student. You might also find my Complete Hematopathology Guide useful; it covers all the main hemepath stuff in a straightforward, no-BS way.

What the H is HLH?

Hemophagocytic lymphohistiocytosis is not easy to pronounce. That’s why it is often abbreviated HLH, which is a lot kinder on both the tongue and the keyboard.

The “hemophagocytic” part of the name, which means “blood + eat + cell,” comes from the observation that the immune activation in HLH often results in hemophagocytosis, in which blood cells are engulfed by histiocytes (macrophages in the tissue) in a very cannibalistic way. Check out the histiocyte in the center of this image (can you see the red cells inside?).

This activation of macrophages is why the disease has also been called macrophage activation syndrome in the setting of juvenile rheumatoid arthritis. The “lympho” part comes from the increase in lymphocytes that happens in HLH. Even though this disease has a complicated name and several different triggers, the symptoms have one common cause: Cytokine Storm.

What causes HLH? Cytokines and hit men.

Cytokines are important molecules in inflammatory signaling in the body, and when not properly regulated they can cause a lot of destruction. if you want a mini-review on cytokines check out all about cytokines in less than 400 words.   

HLH happens when something triggers an over-activation of cytotoxic T and natural killer (NK) cells, which are cells responsible for quickly recognizing and destroying cells which have been infected, usually by viruses. Cytotoxic T cells and NK cells are specialized lymphocytes which are kind of the hit men of the immune system. When they detect cells presenting viral antigens via major histocompatibility complexes, they release perforins to punch holes in the cells and cytokines to signal other inflammatory cells to rush in and finish the job.

This immune over-activation turns on lots and lots of cytokine-producing macrophages. The massive cytokine release causes fever. The huge numbers of activated macrophages end up “eating” or destroying the patient’s own blood cells as well as doing damage to many organs, such as the bone marrow, lungs, and liver. The damaged blood cells get trapped in the spleen, causing splenomegaly. HLH can also kick off other problems in blood regulation, such as disseminated intravascular coagulation (DIC).

Primary vs. Secondary HLH

HLH can be genetic (“primary”) or acquired (“secondary”). Genetic cases usually appear in early childhood and are associated with a mutation affecting cytotoxic cell function, or with an immunodeficiency state such as Chediak-Higashi syndrome. Acquired forms of HLH can occur at any age – but often affect adults (although some adults are later found to have a predisposing mutation). Adult cases are hard to recognize, because they happen in the setting of other serious illnesses and can present with non-specific symptoms.

Acquired HLH can be triggered by any event provoking an immune response. Usually, though, it occurs in the setting of infection or malignancy, when the immune system is already compromised. Infectious triggers are usually viral, most commonly Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Exactly why adult HLH happens in these settings is still poorly understood, although it is thought that underlying genetic susceptibility could play a role in some cases.

Diagnosis

Despite the name of the disease, hemophagocytosis is not necessary to diagnose HLH. It can be helpful  – but it isn’t specific for HLH, and can be found in a lot of other inflammatory conditions. So to diagnose HLH, you need either an established molecular abnormality consistent with an HLH mutation, or 5 of the following clinical criteria:

  1. Fever
  2. Splenomegaly
  3. Cytopenias in at least 2 blood cell lineages (indicating that the blood cells are being eaten up)
  4. High triglycerides and/or low fibrinogen (the latter is involved in the clotting cascade)
  5. Hemophagocytosis
  6. Low or absent NK-cell activity
  7. High ferritin (which transports iron and is also a marker of acute stress in the body)
  8. Elevated soluble CD25 (also called soluble IL-2 receptor alpha. Remember, IL-2 tells lymphocytes to proliferate and differentiate)

Treatment

It is very important to recognize HLH quickly so treatment can be started – but diagnosis can be tricky since many of the symptoms overlap with sepsis or malignancy. Treatment includes chemotherapy, immunosuppression, supportive care, and sometimes bone marrow transplant (mostly in genetic cases). Untreated, HLH is nearly universally fatal.

Bottom Line

The lesson here? Never underestimate the power of cytokines…and think about the possibility of HLH in a very sick patient with the appropriate clinical warning signs.

For more about HLH, read Robbins 9e., pages 585-586

Reference:
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118, 4041–4052 (2011).

A huge thanks to Michelle Stoffel, MD PhD, PGY3 Pathology Resident at the University of Wisconsin, for yet another informative and fun post! Check out her other awesome posts here , here and here