Researchers identify a chromosomal abonormality in leukemia affecting children with Down syndrome

From PRNewswire:

MEMPHIS, Tenn. -- Researchers identified a new chromosomal abnormality in acute lymphoblastic leukemia (ALL) that appears to work in concert with another mutation to give rise to cancer. This latest anomaly is particularly common in children with Down syndrome.

The findings have already resulted in new diagnostic tests and potential tools
for tracking a patient's response to treatment. The research, led by
scientists from St. Jude Children's Research Hospital, also highlights a new
potential ALL treatment. Clinicians are already planning trials of an
experimental medication targeting one of the altered genes.

This study is published in the October 18 online edition of Nature Genetics.

"A substantial proportion of children with ALL lack one of the previously
identified, common chromosomal abnormalities. Also, children with Down
syndrome have an increased risk of ALL, but the reasons why are unclear," said
Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of
Pathology. Mullighan is senior author of the study, which involved scientists
from 10 institutions in the U.S. and Italy. "Our results have provided
important data regarding the mechanisms contributing to leukemia in these
cases," he said.

Instead of the normal pairs of 23 chromosomes, individuals with Down syndrome
inherit an extra copy of one chromosome, in this case chromosome 21.
Chromosomes are made of DNA and carry the genes that serve as the assembly and
operations manual for life. Down syndrome is associated with a variety of
medical and developmental problems, including a 10-to-20--fold increased risk
of ALL. But patients with Down syndrome rarely have the genetic and
chromosomal alterations commonly associated with childhood ALL. Until recently
the genetic basis of the elevated risk for these patients was unknown.

The new gene alteration was identified by St. Jude scientists following up on
an earlier observation. They had previously found a recurring deletion in a
region of DNA duplicated on the X and Y chromosomes. The region is known as
pseudoautosomal region 1 or PAR1.

The PAR1 deletion was found only in patients with a subtype of ALL known as
B-progenitor ALL. It was most common in children with both B-progenitor ALL
and Down syndrome. In this study, investigators screened almost 400 children
with ALL, including 75 patients with Down syndrome. The deletion was present
in 7 percent of patients with B-progenitor ALL, but in more than half of the
patients with both B progenitor and Down syndrome.

The deletion results in a fusion of two genes, P2RY8 and CRLF2. The fusion
puts CRLF2 expression under the control of the P2RY8 promoter. As a result,
CRLF2 expression jumps as much as 10 fold.

"CRLF2 over-expression identifies a group of ALL cases which were not
previously well characterized, and suggests some novel treatment approaches
that may improve patient survival. Patients with Down syndrome are
particularly vulnerable to complications from standard chemotherapy, and could
therefore benefit from novel therapies," said Karen Rabin, M.D., of Texas
Children's Cancer Center and a study co-author. She is a Baylor College of
Medicine assistant professor of pediatric hematology/oncology.

The CRLF2 protein normally forms part of a receptor where a small growth
factor known as a cytokine binds to white blood cells known as lymphocytes.
Both the cytokine, thymic stromal lymphopoietin (TSLP), and CRLF2 are known to
play important roles in the development of immune cells known as T lymphocytes
as well as in inflammation and allergic disease. They had not previously been
linked to leukemia.

CRFL2 is the second gene implicated in development of B-progenitor ALL in
patients with Down syndrome. The first, a gene called JAK2, was identified in
2008. JAK2 belongs to a family of genes that produce enzymes called kinases.
If permanently switched on, kinases can trigger the uncontrolled cell growth
that is a hallmark of cancer.

JAK mutations have also been linked to other cancers. Drugs targeting JAK
kinases are already in clinical trials against a variety of blood disorders in
adults. Additional trials are being planned against other subtypes of
childhood ALL.

In this study, researchers reported a significant association between
alterations in both the CRFL2 and JAK2 genes. Almost all JAK mutations were
observed in patients with CRLF2 alterations. Almost 28 percent of children
with Down syndrome and ALL had changes in both the CRFL2 and JAK genes.

"It has been a mystery as to why the JAK mutations in Down syndrome ALL are
different from those seen in other cancers," Mullighan said. "Here we show
that the JAK mutations in ALL are almost always observed together with a
chromosomal alteration that results in over- expression of CRLF2."

When both the JAK mutation and increased CRLF2 production were introduced into
white blood cells growing in the laboratory, those cells were transformed and
no longer needed cytokines to grow. Neither genetic alteration on its own
produced the same effect. Researchers also reported their impact could be
weakened by the addition of drugs that target JAK mutations.

"We showed that the two proteins, CRLF2 and mutant JAK2, physically interact,
and together transform white blood cells. This work has identified a new
pathway contributing to the development of leukemia," Mullighan said. A next
step is to determine if these mutations also interact in mouse models of ALL.

Other authors of this paper include J. Racquel Collins-Underwood, Letha A.A.
Phillips, Wei Liu, Jing Ma, Elaine Coustan-Smith, Richard T. Williams, Jinjun
Cheng, Ching-Hon Pui, Susana Raimondi and James Downing, all of St. Jude;
Michael L. Loudin of Baylor; Jinghui Zhang of the National Cancer Institute
(NCI); Richard Harvey and Cheryl Willman, of the University of New Mexico;
Fady Mikhail and Andrew Carroll, of the University of Alabama at Birmingham;
Nyla Heerema of Ohio State University; Giuseppe Basso, of the University of
Padua, Padua, Italy; and Andrea Pession of the University of Bologna, Bologna,
Italy.

The work was supported in part by National Cancer Institute, the Bear
Necessities Pediatric Research Foundation, the Children's Cancer Research
Foundation, the National Institutes of Health and ALSAC.