Lausanne: Leukemia affects 350,000 people worldwide. It is a cancer of the white blood cells, which are the cells of the immune system and are produced by stem cells in the bone marrow. There are two types of chronic and two types of acute leukemia. One chronic type, chronic myeloid leukemia accounts for ~20% of all cases, and is caused by a mutated enzyme with unregulated activity. This enzyme comes in two sizes, the second of which is associated with acute lymphocytic leukemia. Being the focus of current leukemia treatment, understanding the role of the enzyme is critical. EPFL scientists have now used proteomics to compare the two forms of the enzyme extensively, uncovering a much clearer view of how it may give different forms of leukemia. The work, published in Leukemia, opens up possibilities for improved drug development and therapy.
myeloid leukemia is caused when two chromosomes in bone marrow stem
cells swap specific parts. The resulting chromosome is called
“Philadelphia”, and now contains a fused gene that produces an abnormal
enzyme called Bcr-Abl.
This enzyme, which is constantly
on, comes into two different sizes, or isoforms: the bigger (p210) is
associated with chronic myeloid leukemia, while the shorter one (p190)
is linked with acute lymphoblastic leukemia, a fast-developing form
that is very difficult to treat leading to death of patients within a
few months. The data on the differences of the two Bcr-Abl isoforms is
inconsistent and confusing, meaning that we need more clarity as to its
role in the development of this type of cancer.
The lab of Oliver Hantschel at EPFL,
in close collaboration with the Proteomics Core Facility at the School
of Life Sciences, used a proteomics approach to study the two isoforms
of Bcr-Abl. Proteomics is a cutting-edge field that uses mass
spectrometry analysis, which enables to map the entire set of proteins
of an organism, termed the proteome.
The researchers looked
at two factors: First, all of the ways each Bcr-Abl isoform interacts
with other molecules in the cell, or its “interactome”. This allowed
them to map out how the two isoforms work with other molecules.
the team looked at the isoforms’ phosphoproteomics. This refers to a
modification — phosphorylation— that many proteins, including Bcr-Abl
undergo in the cell, whereby they are “turned on” with the addition of a
phosphate group. Using mass spectrometry, the researchers were able
identify and compare hundreds of phosphorylated proteins in leukemia
depicting the different signaling networks of the two Bcr-Abl isoforms
determined in this study (credit: Sina Maren Reckel/EPFL)
comparing the two, the researchers were able to map out that there are
“surprisingly large” differences between the interactome and
phosphoproteome of the two isoforms, even though they are both “turned
on” in much the same way. These differences in interactions and
activation could be related to how each isoform drives an entirely
different form of leukemia, and opens up possibilities for
targeting Bcr-Abl in more efficient and effective ways to treat the
This study involved a collaboration of EPFL’s
Swiss Institute for Experimental Cancer Research (ISREC), its
Proteomics Core Facility. It was funded by the ISREC
Foundation, the Swiss National Science Foundation (SNSF) and the
National Center of Competence in Research (NCCR) in Chemical Biology.
Sina Reckel, Romain Hamelin, Sandrine Georgeon, Florence Armand, Qinfang Jolliet, Diego Chiappe, Marc Moniatte, Oliver Hantschel. Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics.Leukemia 23 January 2017. DOI: 10.1038/leu.2017.36