Leading expert in pediatric leukemia, Dr. Shai Izraeli, MD, explains how research into leukemia in children with Down syndrome has revealed critical insights into the fetal origins of cancer and identified a high-risk leukemia subtype driven by JAK/STAT mutations. This discovery has led to the development of targeted therapy clinical trials for a specific group of patients with acute lymphoblastic leukemia, offering new hope for treating this aggressive cancer subtype.
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Understanding High-Risk Acute Lymphoblastic Leukemia and JAK/STAT Targeted Therapy
Jump To Section
- Leukemia and Down Syndrome Link
- Fetal Origins of Childhood Leukemia
- JAK/STAT Mutation Discovery in Leukemia
- High-Risk Leukemia Subtype Identification
- Targeted Therapy Clinical Trials
- Importance of Clinical Trial Participation
- Future of Leukemia Treatment
Leukemia and Down Syndrome Link
Children with Down syndrome have a significantly higher risk of developing leukemia, particularly acute lymphoblastic leukemia (ALL). Dr. Shai Izraeli, MD, explains that this predisposition is linked to the presence of an extra chromosome 21. This additional genetic material fundamentally alters normal blood development during the fetal stage. The disruption in normal developmental processes creates a biological environment that is more susceptible to the initiation of leukemia.
Fetal Origins of Childhood Leukemia
A critical insight from studying leukemia in Down syndrome is that childhood cancer often begins in the fetus. Dr. Shai Izraeli, MD, describes leukemia as a "developmental accident" that occurs during embryonic development. This understanding shifts the perspective on leukemia origins, highlighting it as a problem of abnormal development rather than simply a random cellular malfunction later in life. The research underscores that for many children, the genetic foundations of their leukemia are present at birth.
JAK/STAT Mutation Discovery in Leukemia
The research led by Dr. Shai Izraeli, MD, identified a specific genetic mutation affecting the JAK/STAT signaling pathway as a key driver of leukemia in children with Down syndrome. This mutation acts like excessive fuel to a car's engine, causing cells to proliferate and grow uncontrollably. Remarkably, this same mutation was subsequently found in 5-15% of children and adults with acute lymphoblastic leukemia who do not have Down syndrome. This discovery revealed a common biological mechanism across different patient populations.
High-Risk Leukemia Subtype Identification
The JAK/STAT mutation defines a particularly aggressive form of acute lymphoblastic leukemia. Dr. Shai Izraeli, MD, notes that this subtype represents a high-risk leukemia that is more challenging to treat with conventional chemotherapy regimens. In children with Down syndrome, this mutation appears in 60-70% of ALL cases. For patients without Down syndrome, the frequency is lower (5-15%) but equally significant from a treatment perspective. This classification helps oncologists identify patients who may need more intensive or targeted treatment approaches.
Targeted Therapy Clinical Trials
The identification of the JAK/STAT pathway as a cancer driver has led to the development of targeted inhibitors. Dr. Shai Izraeli, MD, reports that clinical trials are currently underway through the Children's Oncology Group in the United States, involving over 200 institutions worldwide. These trials are testing specific medications designed to block the abnormal signaling caused by the JAK/STAT mutation. This represents a precision medicine approach to leukemia treatment, where therapy is tailored to the specific genetic abnormalities of each patient's cancer.
Importance of Clinical Trial Participation
Dr. Shai Izraeli, MD, emphasizes the critical importance of clinical trial participation for advancing leukemia treatment. He notes that while current treatments cure most leukemia patients, the goal is to cure all patients—which requires focusing on these high-risk subtypes. Dr. Shai Izraeli, MD, acknowledges the uncertainty of new treatments, comparing cancer cells to clever thieves that find new ways to evade therapy. However, he remains encouraged by the rapid translation of basic research discoveries into clinical trials within just nine years.
Future of Leukemia Treatment
The work of Dr. Shai Izraeli, MD, and his colleagues represents the promising future of oncology—where discoveries in specific patient populations yield insights that benefit broader groups of cancer patients. The ongoing clinical trials for JAK/STAT inhibitors may establish a new standard of care for this high-risk leukemia subtype. This research trajectory demonstrates how studying rare conditions can uncover universal biological principles that lead to more effective, targeted cancer therapies for all patients.
Full Transcript
Dr. Anton Titov, MD: You study leukemia in children with Down syndrome. What are the implications of your research for children with leukemia who do not have Down syndrome?
Dr. Shai Izraeli, MD: It's worthwhile to talk about two aspects of leukemia. There are two major findings from the story of leukemia in Down syndrome.
Major finding number one that is generally relevant to childhood leukemia is this: extra chromosome 21 affects normal blood development during the fetal stage, in the embryo. Normal blood development becomes abnormal. It predisposes the children with Down syndrome to leukemia.
Why is this important? Because we know today that childhood cancer in general, and childhood leukemia in particular, already arises in the fetus. Leukemia already exists in the developing embryo.
We know today that leukemia in children is actually an accident. It's a developmental accident. It's an accident in normal development. It's bad luck.
In Down syndrome, this extra chromosome 21 affects the normal development of blood cells. We think, and we have a lot of basis to say this, extra chromosome 21 affects the development of leukemia. This is one important finding.
The second important finding is this: we found that the acute lymphoblastic leukemia of Down syndrome has a specific type of genetic mutation in a specific signalling molecule. I will explain it in more simple terms.
It is a mutation that gives a lot of fuel to the engines of the cell. Cells proliferate and grow. We found that this abnormality is not unique to leukemia in Down syndrome.
It is found also in about 5 to 10% of children and adults with leukemia. These are patients who do not have Down syndrome.
Why is it important? Because there is a cancer medication that blocks this signaling. Now there is a clinical trial in over 200 institutions around the world.
In the Children Oncology Group in the United States, there is an experiment happening. There is a clinical trial with a cancer medication against this type of leukemia.
Many people call such leukemias Philadelphia-like leukemias in children and adults without Down syndrome. Paradoxically, children with Down syndrome are not allowed to participate in these clinical trials, because clinical trials usually exclude children with Down syndrome.
But a very general discovery of a very bad subtype of leukemia resulted from our research. It was our research of leukemia and Down syndrome. We are now trying to cure this leukemia with targeted cancer therapy.
By "we", I mean the whole leukemia treatment community. We have found the driving force of leukemia in about 60 to 70% of the leukemias in Down syndrome. This cancer mutation is the fuel that drives the cancer engine.
Sometimes you think that the leukemic cells are like a car. The driver, or this gasoline, is activation of a signaling pathway. In professional words, we call it JAK/STAT pathway.
We published on importance of JAK/STAT for leukemia in Down syndrome. Then other groups found JAK/STAT mutation also in children and adults with leukemia who do not have Down syndrome. We also found this mutation.
In Down syndrome, 60 or 70% of all cases of acute lymphoblastic leukemia have this mutation. ALL is acute lymphoblastic leukemia.
There are children, adults, and adolescents without Down syndrome who have acute lymphoblastic leukemia. They have JAK/STAT mutation frequency between 5 to 15%. But it's the same leukemia, and it's a very bad type of leukemia.
I said before that we are now in a very good era in treatment of leukemia, because we cure most of the leukemia patients. We want to cure all of the patients with acute lymphoblastic leukemia.
Therefore, we have to focus on high-risk leukemia. The subtype of these leukemias that we identified in Down syndrome is a high-risk leukemia subtype.
Therefore, there are efforts to develop specific inhibitors of this cancer-causing pathway. One of these inhibitors is currently in a clinical trial in the United States in the Children Oncology Group.
I think that they have more than a 100 or 200 different hospitals participating in this clinical trial. It's very important at this stage.
A child might have an acute lymphoblastic leukemia. Then this patient must be involved in a clinical trial, because we really don't know if this treatment will work.
We find often that cancer cells are very tricky. I compare it always to policemen and thieves. You close the door, and they enter through the window.
We don't know if a new cancer therapy against leukemia will help. But I am very encouraged.
We made our discoveries in 2008. About 9 years later, there have been already clinical trials with inhibitors to this acute lymphoblastic leukemia treatment. It's very emotionally exciting!