Hitting Acute Myeloid Leukemia Where It Hurts


Research teams from Massachusetts General Hospital and the Harvard Stem Cell Institute have teamed up to devise a new strategy for treating acute myeloid leukemia (AML). This new strategy is an outgrowth of new findings by these research groups that have identified an enzyme that plays a central role in the onset of AML.

During blood cell development in the bone marrow, hematopoietic stem cells divide to produce daughters cells, one of which remains a stem cells and the other of which becomes a progenitor cell. The progenitor cells can either differentiate toward the lymphoid lineage, in which it will become either a B-lymphocyte, T-lymphocyte, or a Natural Killer cell, or a myeloid precursor that can give rise to neutrophils, megakarocytes (that produce platelets), monocytes, eosinophils, or red blood cells. However, the means by which myeloid cells are formed in the bone marrow of AML patients is abnormal, and the myeloid precursor cells do not differentiate into a specific white blood cells, but, instead, remain immature and proliferate and crowd out and suppress the development of normal blood cells.

David Scadden, MD, director of the MGH Center for Regenerative Medicine (MGH-CRM), co-director of the Harvard Stem Cell Institute (HSCI), and senior author of this Cell paper, had this to say about AML: “AML is a devastating form of cancer; the five-year survival rate is only 30 percent, and it is even worse for the older patients who have a higher risk of developing the disease.” Dr. Scadden continued: “New therapies for AML are extremely limited – we are still using the protocols developed back in the 1970s – so we desperately need to find new treatments.”

What genetic changes cause these developmental abnormalities that lead to AML? As it turns out, a wide range of genetic changes occur in AML (see Medinger M, Lengerke C, Passweg J. Cancer Genomics Proteomics. 2016 09-10;13(5):317-29; and Prada-Arismendy J, Arroyave JC, Röthlisberger S. Blood Rev. 2016 Sep 2. pii: S0268-960X(16)30060-1). In this paper, however, the authors proposed that the effects on differentiation had to transition through a few shared events. Using a method created by lead author David Sykes of the MGH-CRM and HSCI, the team discovered that a single dysfunctional point in the developmental pathway common to most forms of AML that could be a treatment target.

Previous studies had demonstrated that expression of the HoxA9 transcription factor, a transcription factor that must be inactivated during normal myeloid cell differentiation, is actually quite active in the myeloid precursors of 70 percent of patients with AML.  Unfortunately, no inhibitors of HoxA9 have been identified to date.  Therefore, Scadden and others used a different, albeit freaking ingenious, approach to screen small molecules that were potential Hox9A inhibitors based not on their interaction with a particular molecular target but on whether they could overcome the differentiation blockade characteristic of AML cells.

First, they induced HoxA9 overexpression in cultured mouse myeloid cells to design a cellular model of AML.  They also genetically engineered these cultured cells to glow green once they differentiated into the mature white blood cell types.  These groups screened more than 330,000 small molecules to find which would produce the green signal in the cultured cells.  The green glow indicated that the HoxA9-induced differentiation blockade had been effectively overcome. Only these 330,000 compounds, only 12 induced terminal differentiation of these cells, but 11 of then acted by suppressing a metabolic enzyme called DHODH.  DHODH, or dihydroorotate dehydrogenase, is a biosynthetic an enzyme that is a member of the pyrimidine biosynthesis pathway, which catalyzes the oxidation of dihydroorotate to orotate.

dhodh

This is a shocking discovery because the DHODH enzyme is not known to play any significant role in myeloid differentiation.  Corroboratory experiments demonstrated that inhibition of DHODH effectively induced differentiation in both mouse and human AML cells.

The next obvious step would be to use known inhibitors of DHODH in mice with AML.  They were able to identify a dosing schedule that reduced levels of leukemic cells and prolonged survival that caused none of the adverse effects of normal chemotherapy.  Even though six weeks of treatment with DHODH inhibitors did not prevent eventual relapse, treatment for up to 10 weeks seemed to have led to long-term remission of AML.  This remission included reduction of the leukemia stem cells that can lead to relapse.  Similar results were observed in mice into which human leukemia cells had been implanted.

“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target, because it can be complicated and imprecise. We think that with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified,” says Scadden, who is chair and professor of Stem Cell and Regenerative Biology and Jordan Professor of Medicine at Harvard University. Additional investigation of the mechanism underlying DHODH inhibition should allow development of protocols for human clinical trials.

Scadden noted that this manuscript describes six years of work and, also, is a true reflection of the collaborative nature of science in pursuit of clinically relevant therapies.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).