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Better detection of leukemia infiltration in the nervous system

Kiel research team discovers correlations between certain signaling molecules and nervous system involvement in childhood blood cancer

One of the most common cancers in children is acute lymphoblastic leukemia (ALL). This blood cancer originates from malignant degenerated precursor cells of certain white blood cells and usually causes a rapidly progressive reduction in bone marrow function, resulting in impaired hematopoiesis. If left untreated, it can lead to death within a short time. The most common form of this blood cancer in childhood, accounting for around 80 percent of cases, is so-called B-precursor cell ALL (B-ALL); around 600 children are newly diagnosed with this type of cancer in Germany every year. Despite the severity of the disease, those affected today usually have good chances of survival and cure. However, in three to five percent of cases, B-ALL has been shown to affect the central nervous system (CNS) as a serious complication. In addition, it can be assumed that CNS-infiltration is not detected in all patients.

A research team from the Medical Faculty of Kiel University and the Department of Pediatrics and Adolescent Medicine I at the University Medical Center Schleswig-Holstein (UKSH), Kiel Campus, has now investigated which molecular processes are involved in the attack on the nervous system and how this infiltration can be detected more precisely. A specific signal molecule, known as CD79a, appears to play a central role in the growth of B-ALL cells in the CNS. It may also be associated with so-called relapses, i.e. the recurrence of blood cancer after initially successful treatment.  The scientists led by Professor Denis Schewe from the Kiel Oncology Network (KON), together with partner institutions, recently published their findings in the journal Communications Biology.
 

Better diagnosis of CNS infiltration

Although B-ALL is generally well treatable in childhood, there is a risk of CNS involvement. In the vast majority of cases, this is manifested by the leukemia cells settling in particular in the meninges of the affected person. Since the chances of recovery from this complication are reduced and the methods available for determining CNS infiltration are also relatively imprecise, all B-ALL patients are currently treated prophylactically with chemotherapy or a combination of chemotherapy and radiotherapy to prevent the cancer cells from migrating into the CNS. Because of the non-specific effect, which is also toxic to healthy cells, and the resulting possible permanent damage to the nervous system, these forms of treatment are particularly problematic in children.

The research approach of the Kiel scientists promises more precise diagnostics. "We were able to show that the presence of the CD79a molecule in B-ALL cells indicates how well leukemia can establish itself in the central nervous system," explains first author Dr Lennart Lenk, a research associate in the Translational ALL Research Group. "This provides us with a potential new indicator for the presence of leukemia cells in the CNS. The decoding of such molecules, which can improve methods for diagnosing CNS infiltration, would mean that in the future, risky treatment with chemotherapy or radiotherapy would only have to be used if absolutely necessary, precisely because the CNS is actually affected," Lenk continues.
 

Inhibiting the nesting of leukemia in the CNS

In B-ALL, a disturbed development of certain immune cells, the B cells, plays a central role: The disease is essentially based on the fact that the precursor cells, which are not yet functional, cannot turn into mature B cells. Instead, they continue to divide unchecked, flooding the blood and eventually interrupting healthy hematopoiesis. The molecule CD79a functions as a signal molecule of the B cell receptor and is an important part of this disturbed process. Normally, the molecule is rearranged several times during B cell development and eventually reaches the cell surface. The then mature B cell can then assume its normal functioning.

The Kiel research team has now investigated the involvement of CD79a in B-ALL by analyzing samples from patients and using other experimental methods. Using large sample volumes from different biobanks, they were able to confirm that CD79a levels are indeed significantly higher in affected individuals with B-ALL with CNS involvement than in the control group. However, expression of the molecule may not only be suitable as a diagnostic marker. "In various experiments, we were able to show that silencing the molecule greatly reduced the growth of leukemia cells," Lenk says. "It may be that the presence of CD79a itself is a prerequisite for CNS infiltration to occur," Lenk adds.

These new findings suggest that the molecule could be a potential new target for future immunotherapies against B-ALL. "We are therefore currently looking for ways to specifically inhibit the molecule. We have already found promising approaches for this, which now need to be investigated in more detail," emphasizes Schewe, head of the Translational ALL Research Group.

"Our work opens up new perspectives for further research that does not exclusively link leukemia development to cancer-promoting genes or the effect of mutations," explains Dr Ameera Alsadeq, a former collaborator in Schewe's group and currently a scientist at Ulm University Hospital. "In the future, we want to understand more precisely how leukemia cells can instead adapt the expression and function of pre-existing molecules to maintain the disease," Alsadeq adds.

Specifically, in experiments currently underway, the Kiel researchers are testing whether an antibody that targets CD79 and is already in clinical use against other forms of cancer is suitable for this purpose. "Overall, we see the potential on the one hand for more precise diagnosis of CNS involvement in B-ALL patients and on the other hand for future treatment approaches in the form of novel immunotherapies that could be based on inhibition of the signal molecule," Schewe summarizes.

"The new results from Professor Schewe's research group show a valuable perspective for combating this particularly common blood cancer disease in children in the future. The work in the Translational ALL Research Group is therefore exemplary for the efforts in the entire Kiel cancer research network to achieve the most direct possible transfer of promising research results into clinical application," emphasizes Professor Susanne Sebens from the Institute for Experimental Tumor Research at Kiel University and spokesperson of the Kiel Oncology Network.

About the Kiel Oncology Network (KON)
The KON was established in 2013 as part of the Kiel University's priority research area Kiel Life Science, with the goal of linking the research activities of as many basic and clinically-orientated oncology researchers as possible, and promoting cooperation between them. As such, KON incorporates a broad spectrum of long-term and excellent expertise in oncology, including tumour biology, genetics and epigenetics, immunology, pharmacology, pathology, structural biology as well as modern medical imaging. KON's vision is to gain a significantly better understanding of all the important steps in tumour evolution, as well as resistance mechanisms to cancer treatment, by using comprehensive and multidisciplinary analysis strategies. This knowledge could provide a basis for the development of innovative diagnosis and treatment strategies, to decisively improve the prognosis for and survival of cancer patients.

More information:

Three persons in a laboratory
© Christian Urban, Kiel University

Professor Denis Schewe, Dr Fotini Vogiatzi and Dr Lennart Lenk (left to right) are investigating the role of the signaling molecule CD79a in leukemia attacking the central nervous system.

[Translate to English:] Histologic images of the brain
© Dr Lennart Lenk

Compared with a CNS-negative case (left), where no leukemia cells have invaded the meninges (marked in blue), CNS infiltration (right) is shown clearly by the appearance of leukemia cells in the meninges (marked in red).

Original publication:

Lennart Lenk, Michela Carlet, Fotini Vogiatzi, Lea Spory, Dorothee Winterberg, Antony Cousins, Michaela Vossen-Gajcy, Olta Ibruli, Christian Vokuhl, Gunnar Cario, Omar El Ayoubi, Lisa Kramer, Matthias Ritgen, Monika Brüggemann, Robert Häsler, Martin Schrappe, Stephan Fuhrmann, Christina Halsey, Irmela Jeremias, Elias Hobeika, Hassan Jumaa, Ameera Alsadeq, Denis M. Schewe (2021): CD79a promotes CNS-infiltration and leukemia engraftment in pediatric B-cell precursor acute lymphoblastic leukemia. Communications Biology First published on 15. January 2021
DOI: 10.1038/s42003-020-01591-z

 

Contact:

Dr Lennart Lenk
Translational ALL-Research Group
Department of Pediatric and Adolescent Medicine I
Faculty of Medicine, Kiel University / UKSH
+49 (0) 431 500-20224
lennart.lenk@uksh.de

 

Press contact:

Christian Urban
Science communication „Kiel Life Science",
Kiel University:
+49 (0) 431-880-1974
curban@uv.uni-kiel.de

 

Prof. Dr. Denis Schewe
Head Translational ALL-Research Group
Senior physician for hematology, oncology, stem cell transplantation
Department of Pediatric and Adolescent Medicine I
Faculty of Medicine, Kiel University / UKSH
+49 (0) 431 500-20140
denis.schewe@uksh.de