Happy St. Patrick’s Day, everyone! In celebration of the lovely cloverleaf, we have a guest post from our esteemed medical student and frequent contributor, Richard Huang. Take it away, Richard.

The image above shows a number of flower cells that are pathognomonic of HTLV-induced adult T cell leukemia (ATL). They have absolutely nothing to do with today, St. Patrick’s Day, except that the multilobed nucleus of an ATL cell looks like a cloverleaf, which gives me an excuse to write about them. In fact, such cells are officially named cloverleaf cells or flower cells. (Another interestingly named cell is the “faggot cell“ of acute promyelocytic leukemia.)

The 1970s is best known for its drugs, sex, and rock and roll, a culture that is popularly summed up by the slogan “flower power.” Little did people know how medically appropriate that slogan would be, since the 1970s marked the beginning of one of the biggest scientific discoveries: retroviruses. While the most famous retrovirus to date is the human immunondeficiency virus (HIV), the very first human retrovirus discovered was the human T cell lymphotrophic virus (HTLV).

HTLV can infect various types of cells, including B cells, monocytes, and fibroblasts. The GLUT1 transporter has been identified as a receptor for HTLV, so theoretically, HTLV can infect any cell that uses that particular transporter. However, as the virus’s name suggests, the main cell target is T cells (both CD4+ and CD8+).

One very interesting thing about HTLV is that it spreads within the host via cell-to-cell transmission using virus-induced cell-to-cell synapses (rather than the traditional mechanisms of viral shedding, such as budding, exocytosis, and apoptosis). Consequently, acute HTLV infection is rarely detected using serum viral loads. HTLV infections are usually latent and asymptomatic, and usually do not cause disease until decades later.

The spectrum of diseases caused by HTLV is broad. It includes benign diseases such as dermatitis, more serious diseases like HTLV-associated myelopathy (HAM), and deadly diseases such as the rapidly-fatal adult T cell leukemia (ATL).

The most important viral protein in the oncogenesis of ATL is the functionally pleiotropic viral protein Tax, which both promotes the proliferation of and inhibits the apoptosis of infected T cells by:

1. stimulating the production of cytokines IL-2 and IL-15, which are growth factors that cause clonal expansion of T cells
2. facilitating the methylation, and consequently suppression, of the p16 gene, the product of which normally blocks the cell cycle by inhibiting cyclin dependent kinase 4 (CDK4)

For a quick rundown of cytokines and how to memorize them, check out these excellent articles on PathologyStudent.com: All about cytokines in less than 400 words and How to memorize interleukins.

Immunophenotypically, ATL cells have a characteristic profile. The cells are typically:

1. strongly positive for CD4 or CD8, CD25 (alpha chain of IL-2 receptor), and CD2 (a T cell surface adhesion molecule)
2. negative for myeloid (CD13, CD33) and B cell lineage (CD10, CD19, CD20, CD21, CD22) markers

For an excellent overview on CD markers, I highly recommend the follow the primer A short list of CD markers and Dr. Kraft’s book “The Complete (but not obsessive) Hematopathology Guide.”

Despite all we know about the involvement of Tax protein and cytokines in ATL, the definitive diagnosis of this disease is still made by seeing flower cells on peripheral blood smears and detecting HTLV within these cells.