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Study overturns basic tenet in leukemia biology

Findings could lead to better therapies for acute myeloid leukemia, among most difficult cancers to treat
woman looking into microscope with images of cells on screen to her left
Anupriya Agarwal, Ph.D., in the OHSU School of Medicine and researcher with the OHSU Knight Cancer Institute, is first author on a new study that finds a basic premise about steps leading to AML are unsound. (OHSU/Kristyna Wentz-Graff)

Scientists thought they understood the steps leading to acute myeloid leukemia. But one of the basic tenets in that understanding turns out to be unsound, according to researchers at the OHSU Knight Cancer Institute.

Acute myeloid leukemia, or AML, is the most common blood cancer in adults – and one of the most difficult to treat. The new findings explain why promising treatment approaches may have fallen short. And the results could help guide efforts to develop more effective therapies for the cancer.

Myeloid stem cells in the bone marrow are supposed to mature, or differentiate, to become red blood cells, immune system white blood cells, or clot-forming platelets. These blood cells are short-lived and to maintain populations the bone marrow has to make millions of new blood cells per second.

In people with AML, this massive and tightly regulated output of mature blood cells collapses. Immature stem cells multiply rapidly and reach overwhelming numbers in the bone marrow, blood circulation and other organs.

Textbook explanations specify that various genetic alterations seen in AML conspire to block the differentiation of myeloid stem cells at an immature stage, along with increased proliferation of these cells.

agarwal, working with pipette under the hood at a chemistry bench
“Multi-disciplinary approaches, along with technological advancement, will unravel new things, but if you go back to answer old questions you may find different answers,” said first author Agarwal. (OHSU/Kristyna Wentz-Graff)

But the Oregon Health & Science University researchers showed that differentiation of stem cells is not actually blocked in AML. Instead, they found that just a slight skewing of the fraction of cells that differentiate is enough to cause an overwhelming buildup of immature stem cells, called myeloid blasts. The findings suggest that therapies designed to slightly adjust the differentiation of stem cells could be a way forward.

“Multi-disciplinary approaches, along with technological advancement, will unravel new things, but if you go back to answer old questions you may find different answers,” said first author Anupriya Agarwal, Ph.D. “You may get surprised.” Agarwal is an associate professor in the OHSU School of Medicine. The paper presenting the research was published in Proceedings of the National Academy of Sciences.

‘Normal blood cell production must be on a knife’s edge of being leukemic to work as it does’

The discovery started with a mathematical model that simulates the dynamics of blood cell production. For each type of cell, the model accounts for total cell number, single cell death rate, single cell division rate, and the probability that each daughter cell differentiates into a particular type of cell.

Brian Druker, M.D. (2017)
Brian Druker, M.D.

Bill Bolosky, Ph.D., a computer scientist at Microsoft Research Lab in Redmond, Washington, worked up the original model with mathematician David Wilson, Ph.D., at the University of Washington. Agarwal said she and senior author Brian Druker, M.D., happened to see a presentation by Bolosky and wondered if his model could be used to answer questions about the putative blocking of differentiation in AML.

Using the model, the researchers derived a typical value for the rate of differentiation of stem cells into mature blood cells. They found that very slight reductions in the differentiation rate were all that were needed for the number of immature cells to grow without bound, “suggesting normal blood cell production must be on a knife’s edge of being leukemic to work as it does,” in the words of the paper.

“It is not a complete block to differentiation, but a small change in the balance between differentiation and self-renewal,” said Druker, director of the Knight Cancer Institute and JELD-WEN Chair of Leukemia Research in the OHSU School of Medicine.

Blood samples given by 12 patients with AML allowed the researchers to test and validate the model results. They sorted the mature from the immature myeloid cells in the patient blood samples. Leukemia-causing gene alterations thought to block differentiation were present at similar levels in both mature and immature myeloid cells – strong evidence to overturn the paradigm that these AML gene alterations fully block differentiation.

“This is an example of how collaborations work and how bringing people working in different disciplines allow advances to be made,” Druker said. “It also shows the importance of being flexible in considering possibilities, and being willing to test radical new ideas.”

The work helps explain why drugs designed to drive differentiation of blood cells are not very effective against AML. Developing new therapies with stronger activity will require deeper understanding of specific mechanisms underlying reduced or skewed differentiation in genetic subtypes of the disease. The authors said the model could aid in understanding the effects of drugs designed to act on blood cell differentiation.

AML research
The discovery suggests that new therapies could be designed to slightly adjust the differentiation of stem cells could be a possible way forward. (OHSU/Kristyna Wentz-Graff)

This study was supported by Howard Hughes Medical Institute Investigator funding and Beat AML funding from the Leukemia & Lymphoma Society to Brian Druker; and by NIH, V Foundation Scholar Award, American Cancer Society Research Scholar Grant and Knight Pilot Project Award funding to Anupriya Agarwal.

Brian Druker reports the following potential competing interests: scientific advisory board member with Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), and Monojul (inactive); SAB and stock holdings with Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), and CTI BioPharma (inactive); scientific founder of MolecularMD (inactive, acquired by ICON); board of directors member and holdings with Amgen; board of directors member with Burroughs Wellcome Fund, CureOne; joint steering committee member with Beat AML LLS; founder of VP Therapeutics; clinical trial funding from Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and Oregon Health & Science University and Dana-Farber Cancer Institute (one Merck exclusive license).


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