Why BMTs can fail in MPDs (today at 3:00 PM)
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Memo To Me
Apr 1, 2021, 2:00:15 PM4/1/21
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http://www.mpdsupport.org Pre-Cancerous Blood Diseases Can Be Products Of Their Environment When blood-forming stem cells misbehave, causing pre-cancerous conditions that can sometimes even progress to leukemia, the problem might not always lie with them. Rather, two studies in the journal Cell, published by Cell Press, reveal that a bad environment might be to blame.
Both reports show that defects in the bone marrow - where blood cells are made - can spawn such pre-cancerous blood disorders in mice. Previously, such myeloproliferative syndromes were thought to be rooted in the blood cells themselves.
"We show that the bone marrow microenvironment can make the blood cells become abnormal, like a type of pre-leukemic disease," said Louise Purton, who is affiliated with Peter MacCallum Cancer Centre in Australia, Massachusetts General Hospital, and the Harvard Stem Cell Institute. Such pre-cancerous conditions are often difficult to treat in humans, she added, mainly because not much is known about what causes the blood cells to act out.
"The defect we see isn't intrinsic to the blood cells themselves," added Stuart Orkin, a Howard Hughes Medical Institute investigator at Children's Hospital Boston and Chairman of Pediatric Oncology at the Dana-Farber Cancer Institute. "It's a result of the interaction of the blood and support cells in bone marrow. We didn't predict that at all."
In addition to its important role in regulating the self-renewal and differentiation of blood stem cells, also known as hematopoietic stem cells (HSCs), the bone marrow microenvironment has been proposed to consist of various other niches or hematopoietic inductive microenvironments - areas of the bone marrow that are highly specialized for the development of different kinds of maturing hematopoietic cells, Purton explained. This concept has been supported by the recent identification of specific niches for blood cells including B lymphocytes and megakaryocytes in the bone marrow, she said.
Purton's team found in an earlier study that mice lacking the retinoic acid receptor RAR one of three receptors that respond to a derivative of vitamin A, experience a 3-fold reduction in the number of HSCs. Now, her team has found that the animals also develop myeloproliferative disease, in which the stem cells in bone marrow produce too many blood cell progenitors and blood cells.
Unexpectedly, they reported, transplant studies revealed that this disease was caused by the bone marrow deficiency. Bone marrow from healthy mice transplanted into mice with the RAR-deficient microenvironment rapidly developed the blood disease, they showed, evidence that the microenvironment can be the sole cause of hematopoietic disorders.
Meanwhile, Orkin's team set out to examine the role of so-called retinoblastoma protein (Rb) - a critical player in controlling the cell cycle - in blood cell development.
"In the absence of Rb, blood stem cells leave the bone marrow and end up in the spleen and other places," Orkin said. "It deregulates the process
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Both reports show that defects in the bone marrow - where blood cells are made - can spawn such pre-cancerous blood disorders in mice. Previously, such myeloproliferative syndromes were thought to be rooted in the blood cells themselves.
"We show that the bone marrow microenvironment can make the blood cells become abnormal, like a type of pre-leukemic disease," said Louise Purton, who is affiliated with Peter MacCallum Cancer Centre in Australia, Massachusetts General Hospital, and the Harvard Stem Cell Institute. Such pre-cancerous conditions are often difficult to treat in humans, she added, mainly because not much is known about what causes the blood cells to act out.
"The defect we see isn't intrinsic to the blood cells themselves," added Stuart Orkin, a Howard Hughes Medical Institute investigator at Children's Hospital Boston and Chairman of Pediatric Oncology at the Dana-Farber Cancer Institute. "It's a result of the interaction of the blood and support cells in bone marrow. We didn't predict that at all."
In addition to its important role in regulating the self-renewal and differentiation of blood stem cells, also known as hematopoietic stem cells (HSCs), the bone marrow microenvironment has been proposed to consist of various other niches or hematopoietic inductive microenvironments - areas of the bone marrow that are highly specialized for the development of different kinds of maturing hematopoietic cells, Purton explained. This concept has been supported by the recent identification of specific niches for blood cells including B lymphocytes and megakaryocytes in the bone marrow, she said.
Purton's team found in an earlier study that mice lacking the retinoic acid receptor RAR one of three receptors that respond to a derivative of vitamin A, experience a 3-fold reduction in the number of HSCs. Now, her team has found that the animals also develop myeloproliferative disease, in which the stem cells in bone marrow produce too many blood cell progenitors and blood cells.
Unexpectedly, they reported, transplant studies revealed that this disease was caused by the bone marrow deficiency. Bone marrow from healthy mice transplanted into mice with the RAR-deficient microenvironment rapidly developed the blood disease, they showed, evidence that the microenvironment can be the sole cause of hematopoietic disorders.
Meanwhile, Orkin's team set out to examine the role of so-called retinoblastoma protein (Rb) - a critical player in controlling the cell cycle - in blood cell development.
"In the absence of Rb, blood stem cells leave the bone marrow and end up in the spleen and other places," Orkin said. "It deregulates the process
\\\\ To post or reply, email to: MPDSU...@LISTSERV.ICORS.ORG ////
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