Transient myeloproliferative disease

Last updated
Transient myeloproliferative disease
Other namesTransient abnormal myelopoiesis (TAM), transient leukemia, myeloid leukemia of Down syndrome

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses [1] as well as infants in their first few months of life. [2]

Contents

Transient myeloproliferative disease involves the excessive proliferation of non-malignant megakaryoblasts. Megakaryoblasts are hematological precursor cells which mature to megakaryocytes. Megakaryocytes release platelets into the bloodstream. Platelets are critical for normal blood clotting. [3] In consequence of this mutation, megkaryoblasts fail to mature properly, accumulate in multiple organs, may damage these organs, and may become cancerous. The diseases also causes a reduction in the maturation of erythroblasts to circulating red blood cells and, consequently, mild anemia. [4]

Most individuals with TMD have clinical evidence of damage to various organs, particularly the liver, due to megakaryoblast infiltration, the accumulation of fluid in various tissue compartments, a bleeding tendency due to low levels of circulating platelets (i.e. thrombocytopenia), anemia due to reduced production of red blood cells, and/or other signs or symptoms of the disorder. [5] However, some individuals with transient myeloproliferative disease have a presumably small clone of rapidly proliferating megakaryoblasts with inactivating GATA1 mutations but no other signs or symptoms of the disease. This form of TMD is termed silent transient abnormal myelopoiesis (i.e. silent TAM). Silent TAM is of clinical significance because it, like symptomatic TMD, may progress to an acute megakaryoblastic leukemia. This progression occurs in ~10% of TMD cases at some time during the 4-5 following birth and is due to the acquisition by the rapidly proliferating megakaryoblast clones of oncogenic mutations in other genes. [2]

Chemotherapeutic regimens are used to treat individuals with TMD but only those who have life-threatening complications of the disease. It is not known if these regimens have an impact on the development of acute megakaryoblastic leukemia. Currently, it is recommended that individuals with TMD be followed medically for signs, symptoms, or laboratory evidence of its progression to this malignant disease with the notion that its early treatment may be of clinical benefit. [2]

Signs and symptoms

Before birth

Transient myeloproliferative disease develops and may be of concern in fetuses. Features in a review of 39 reported fetal cases include: reduced platelet production often accompanied by significantly reduced levels of circulating platelets; reduced red blood cell production sometimes accompanied by mild anemia; increased levels of circulating megakaryoblasts and white blood cells; grossly enlarged liver and liver dysfunction due to an excessive accumulation of platelet precursor cells; enlarged spleen presumed due mostly to the portal hypertension accompanying liver disease with extramedullary hematopoiesis possibly contributing to the enlargement; accumulation of excessive fluid in bodily compartments such as the pericardial, pleural, abdominal spaces; hydrops fetalis, i.e. the accumulation of excessive fluid in two or more bodily compartments; cardiomegaly and other cardiac abnormalities resulting form atrial septal defects, small ventricular septal defects, and/or, possibly, accumulation of megakaryocytes and secondary cardiac fibrosis. [1] Hydrops fetalis, when accompanied by liver dysfunction, is a particularly poor prognostic combination in TMD. [6]

After birth

Symptomatic disease

Clinical features in a review of 3 studies reporting on a total of 329 cases of symptomatic TMD include: premature birth (33-47%); enlarged liver (55-62%); evidence of liver dysfunction (13-63%); enlarged spleen (36-44%); heart disease (47-71%); gastrointestinal abnormalities (1-25%); and fluid accumulations in lung, heart, and/or abdomen (16-21%). In other studies; 5% of cases were associated with a vesiculopapular eruption; 3-6% of cases were associated with kidney failure or insufficiency presumed due mostly to complications of cardiac and/or liver dysfunction; rare cases of lung dysfunction due primarily to its compression by a massively enlarged liver and/or fluid accumulations in the pleural space; [2] and rare cases of asymptomatic megakaryoblastic infiltration and secondary fibrosis in the pancreas. [5] Other reports find decreased levels circulating platelets in 50% of cases, abnormal blood clotting in 10-25% of cases, anemia in 5-10%, and increased levels of circulating white blood cells in 50% of cases. The incidence of all these features except for low levels of blood platelets are appreciably higher in TMD than in Down syndrome individuals that lack inactivating GATA1 mutations. [2] There are also uncommon instances of stillbirths and infant death within 24 hours of delivery. [1]

Silent disease

Silent TAM lacks almost all of the clinical features of TMD, i.e. newborns with this disease exhibit no signs or symptoms that differ from those found in Down syndrome individuals who lack inactivating GATA1 mutations. Silent TAM nonetheless carries the threat of progressing to AMKL with an incidence similar to that occurring in TMD. [2]

Genetics

Down syndrome

Down syndrome is caused be the presence of an extra chromosome 21 (i.e. trisomy 21) due to a failure in normal chromosomal pairing or premature unpairing during the cell division of meiosis in egg or sperm cells. In these cases, virtually all cells in Down syndrome individuals bear an extra chromosome 21. However, there are other genetic changes that may either cause Down syndrome or cause an individual without Down syndrome to bear disease susceptibilities of the syndrome. These genetic changes include: a) genetic mosaicism in which some body cells bear a normal chromosome complement while others bear an extra chromosome 21; b) a part of chromosome 21 is located on another chromosome due to a Robertsonian translocation; c) partial trisomy 21 in which only part of chromosome 21 is duplicated; d) an isochromosome in which chromosome 21 contains two long but no short arms; and e) key genes on chromosome 21 are duplicated on this or other chromosomes. [7] These genetic changes do occur in rare cases of individuals who do not have Down syndrome but nonetheless develop transient myeloproliferative disease [8] due to the presence of extra copies of key genes normally found on chromosome 21 genes caused by mosaic, Robertsonian translocation, partial trisomy 21, isochromosome formation, or duplication. [5]

Down syndrome by itself (i.e. in the absence of GATA1 gene mutations) is a cause for numerous hematological abnormalities which are similar to those seen in TMD. These Down syndrome-related abnormalities include increased numbers of stem cell precursors to platelets and red blood cells, impaired maturation of these precursors to platelets and red blood cells, thrombocytopenia, abnormal bleeding, anemia, leukocytosis, and serious liver damage. Since TMD is restricted to individuals with Down syndrome or otherwise have an excess of key chromosome 21 genes, it is suggested that certain chromosome 21 genes that are in triplicate and cause these hematological disorders in Down syndrome are essential for the development of GATA1 inactivating mutations and thereby TMD. These genes include ERG , a potentially cancer-causing oncogene that codes for a transcription factor; DYRK1A , which codes for a protein kinase type of enzyme involved in promoting cellular proliferation; and RUNX1 , which codes for a transcription factor that regulates the maturation of hematological stem cells and, when mutated, is involved in the development of various myeloid neoplasms. [2]

Transient myeloproliferative disease

The human GATA1 gene is located on the short (i.e. "p") arm of the X chromosome [9] at position 11.23. [10] It is 7.74 kilobases in length, consists of 6 exons, and codes for a full length protein, GATA1, of 414 amino acids (atomic mass=50 kilodaltons) and a shorter protein, GATA1-S (also termed GATA1s). GATA1-S lacks the first 83 amino acids of GATA1 and consists of 331 amino acids (atomic mass = 40 kilodaltons). [11] GATA1 and GATA1-S are transcription factors, i.e. nuclear proteins that regulate the expression of genes. [9] The genes targeted by these two transcription factors help control the maturation of megakaryoblasts and promegakaryocytes to platelet-forming megakaryocytes [11] and the maturation of erythroblasts to red blood cells. [12] GATA1-S is less active than GATA1 in controlling most of these genes including those that stimulate megakaryoblast maturation but appears more effective than GATA1 in stimulating megakaryoblast proliferation. [11] Outside of the Down syndrome (or a triplication in key chromosome 21 genes), GATA1 inactivating mutations cause or contribute to various non-malignant X-linked bleeding and anemic disorders that are due to failures in the maturation of precursor cells to platelets and red blood cells. [4]

The GATA1 mutations in Down syndrome cause TMD. They occur in exon 2 or 3 of the gene and are truncating mutations that result in the gene's exclusive formation of GATA1-S, i.e. the gene makes no GATA1. [11] Some 20% of individuals with Down syndrome bear one truncating mutation although some may bear up to 5 different truncating mutations and therefore have 5 different GATA1 mutant clones. These mutations occur in utero and can be detected in fetuses of 21 weeks gestational age. In the absence of GATA1, the GATA1-S transcription factor increases the proliferation but not maturation of megakaryoblasts [4] and is insufficient to support the normal maturation of red blood cell precursors. [13] Consequently, fetuses [1] and, during their first few months of live, infants [2] with these mutations exhibit extensive accumulations of immature megakaryoblasts in fetal blood-forming organs (particularly liver and bone marrow) and decreases in circulating platelet counts; they may also exhibit modest reductions in circulating red blood cells; and they may exhibit severe injuries in various organs. In ~80% of individuals, hematological changes resolve completely within ~3 months although organ injuries, particularly those to the liver, may take months or even years to fully resolve. During this resolution period, GATA1 mutations become undetectable. However, the original mutations are again detected in the acute megakaryoblastic leukemia cells indicating that the GATA1 mutations causing TMD decrease to undetectable levels as TMD resolves but, at least in cases that progress to AMKL, persist in a tiny clone of megakaryoblasts that evolve into the malignant cells of AMKL. In most cases, this evolution occurs over 1–5 years but in ~20% of cases the in utero [1] or postnatal disease [3] is severe, prolonged, and/or fatal or progresses to AMKL without exhibiting a resolution phase.[ citation needed ]

The GATA1 gene also regulates the maturation of eosinophils and dendritic cells. Its impact on the former cell type may underlie the increase in circulating blood eosinophils in TMD. [12]

Acute megakaryoblastic leukemia

TMD may be followed within weeks to ~5 years by a subtype of myeloid leukemia, acute megakaryoblastic leukemia. AMKL is extremely rare in adults. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without Down syndrome. The disease in Down syndrome occurs in ~10% of individuals who previously had TMD. [14] During the interval between TMD and the onset of AMKL, individuals accumulate multiple somatic mutations in cells that bear an inactivating GATA1 mutation plus trisomy 21 (or the presence of extra chromosome 21 genes involved in the development of TMD). These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the GATAT1 mutation in the presence of trisomy 21 (or the presence of extra chromosome 21 genes involved in the development of TMD) and to be responsible for progression of the transient disorder to AMKL. The mutations occur in one or more genes including: TP53, FLT3, ERG, DYRK1A, CHAF1B, HLCS, RUNX1, MIR125B2 (which is the gene for microRNA MiR125B2CTCF, [3] STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS , and SH2B3. [14]

Pathophysiology

The development and progression of TMD result from collaborations between various genes: 1) during fetal development, an immature megakaryoblast which has extra copies of key genes located on chromosome 21 (e.g. ERG, DYKR1A, and/or RUNX1) acquires an inactivating mutation in GATA1 that causes it to make only GATA1-S; 2) this cell(s) grows into a genetically identical group, i.e. a clone, of non-malignant megakaryoblasts which proliferate excessively, fail to mature normally, and over-populate fetal blood-forming organisms, particularly the liver and bone marrow, thereby establishing TMD; 3) most cells in this clone are still genetically programmed to die during the ensuing fetal and early postnatal period thereby resolving TMD; 4) some cells in this GATA1-mutant clone escape the death program although their numbers are too low for detection by current methods; 5) in ~10% of TMD cases, the surviving cells from the GATA1 mutant clone undergo an evolution to cancer, i.e. they acquire mutations in other genes (see preceding section) which causes at least one of them to be malignant, immortal, and rapidly proliferating thereby founding a clone of megakaryoblasts that have the original GATA1 mutation, extra chromosome 21 genes, and one or more one of the newly acquired oncogenic gene mutations; and 6) the cells in this malignant clone infiltrate, accumulate in, and injure various organs and tissues thereby establishing AMKL. [2] [7] These stages in the development and progression of TMD may involve up to 5 different GATA1 gene mutations in different megakaryoblasts and therefore result in the evolution of up to 5 different GATA1-mutant clones, at least one of which may found the malignant clone involved in AMKL. [4]

The severity of transient myeloproliferative disease appears to depend on the size of the GATA1 mutant clone. It is likely, for example, that the lack of clinical features in silent TAM is a reflection of the small size of its mutant GATA1 clone. [2]

The liver of TMD-individuals accumulate abnormally high numbers of platelet and -to a lesser extent- red blood cell precursors. The liver, it is suggested, may be the primary site for excessive proliferation of the GATA1 mutant clone(s) of platelet precursor cells, primarily megakaryobllasts and the accumulation of these precursor cells along to red blood cell precursor cells appears to be an important cause of the liver enlargement and dysfunction occurring in TMD. [14]

TMD is associated with fibrosis (i.e. replacement of normal tissue with fibrous tissue) in the liver. This fibrosis may be severe and even life-threatening. [15] Based primarily on mouse [16] and isolated human cell studies, [17] this myelofibrosis is thought to result from the excessive accumulation of mutant GATA1-bearing platelet precursor cells in these organs: the precursor cells make and release abnormally large amounts of cytokines (platelet-derived growth factor; transforming growth factor beta 1) which stimulate tissue stromal cells to become fiber-secreting fibroblasts.

Diagnosis

Fetuses [1] and newborns [2] with Down syndrome without GATA1 inactivating mutations have numerous hematological abnormalities some of which are similar to those in TMD including increased numbers of circulating blasts, decreased numbers of circulating platelets and red blood cells, and increased numbers of circulating white blood cells. Also like TMD, these Down syndrome (no GATA1 mutation) individuals exhibit hepatomegaly, abnormal liver function tests, and jaundice. However, these abnormalities are usually more frequent and/or severe in TMD. Furthermore, enlarged spleen, fluid accumulations in body cavities, and leukemia cutis (i.e. a rash due to the infiltration of platelet precursor cells into the skin) occur in ~30, 9, and 5%, respectively, of TMD cases but are rarely observed in individuals with Down syndrome (no GATA1 mutation). The blood of individuals with TMD may contain grossly malformed blast cells, giant platelets, and fragments of megakaryocytes which are rarely seen in individuals with Down syndrome (no GATA1 mutation). Bone marrow examination reveals increases in blast cells in essentially all cases of TMED, increased fibrosis in a small but significant percentage of cases, defective maturation of platelet precursors in ~75% of cases, and defective maturation of red blood cell precursors in 25% of cases. These abnormalities are generally more extreme that those seen in Down syndrome (no GATA1 mutation). The overall constellation of abnormalities found in TMD often suggest its diagnosis. [5]

In all individuals suspected of having the symptomatic or silent disease, the diagnosis of TMD requires demonstrating the presence, in the platelet precursor cells of blood, bone marrow, or liver, of GATA1 mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors. Since these mutations are limited to a clone(s) of platelet precursor cells which may represent only a small fraction of all platelet precursor cells, high-throughput DNA sequencing methods are required to detect many cases of the disease, particularly in silent TAM cases which may have only a small number of platelet precursors with the mutation. [2] The in utero diagnosis of fetal TMD depends on medical ultrasound scanning to detect fluid accumulations in body cavities, cardiac abnormalities (particularly atrial septal defects), organ enlargements (particularly of the liver, spleen, or heart), fetal size, and fetal movements. Blood samples are obtained from the fetal umbilical cord to determine blood cell counts, measure blood enzymes to evaluate liver function, and the presence in circulating platelet precursor cells of GATA1 mutations that are associated with TMD. [1]

Treatment

Since 80 to 90% of newborns with transient myeloproliferative disease recover within ~3 months (organ enlargement make take longer to resolve), treatment is generally restricted to cases with life-threatening complications. These complications include severe: a) hydrops fetalis; b) increases in circulating white blood cells (e.g. >10-fold elevations) that can lead to a blood disorder termed the hyperviscosity syndrome; c) bleeding due to disseminated intravascular coagulation or, less commonly, reduced levels of circulating platelet; d) liver dysfunction; or e) cardiac dysfunction. There have been no large controlled studies published on treatment but several small studies report that low dose cytarabine, a chemotherapeutic drug, has beneficial effects in these cases. High dose cytarabine, however, has been found to be highly toxic in infants with TMD; it is recommended that these dosages be avoided in TMD. The goal of low dose cytarabine in TMD is to reduce the load but not eradicate platelet precursors in tissues and/or circulating megakaryoblasts or, in cases of extreme leukocytosis, white blood cells, particularly since none of these cells are malignant. [2] [5] There is insufficient data to indicate the value of therapy in prenatal cases. Supportive fetal therapy consisting of repeated in utero transfusion of packed red blood cells and platelet concentrates has been reported to reduce the proportion of circulating blast cell, reduce fluid accumulations in fetal cavities, and reduce the size of an enlarged liver; preterm induction of delivery has also been used in infants with fetal distress. However, further studies are required to determine the clinical usefulness of these and other interventions in prenatal TMD. The Cochrane Organization rated the quality of evidence for these fetal interventions as very low. [1]

Experts suggest that individuals with symptomatic or silent TMD be followed medically for signs and/or symptoms of the disease's progression to AMKL. This includes physical examinations to measure liver and spleen size as well as complete blood counts to measure the levels of circulating platelets, erythrocytes, white blood cells, and platelet precursor cells. Recommendations for the frequency of these measurements vary from every 3 to 12 months. [2] A complex drug regimen that includes high dose cytarabine [18] has shown good results in treating AMKL. [2]

Prognosis

Overall mortality during the first year as reported in three studies (all of which included individuals treated for their TMD), range between 15 and 21% in TMD and between 4 and 12% in Down syndrome (no GATA1 mutation). Virtually all of the deaths occurring in TMD happened within the first 6 months. Risk factors that increased mortality in TMD were prematurity, extremely elevated circulating blast and/or white blood cells, hepatic dysfunction, ascites (i.e. fluid in the abdominal cavity), excessive bleeding and/or blood clotting, and kidney dysfunction. [5] About 10% of all TMD cases, including those with silent disease, will progress to AMKL at some time during the first 5 years after birth. AMKL associated with Down syndrome is far less severe a disease that AMKL not associated with the syndrome. Event free survival and overall survival (studies include chemotherapy-treated cases) during the 5 years following its diagnosis in Down syndrome children with AMKL is ~80%; it is 43% and 49%, respectively, in children with AMKL who do not have Down syndrome. Median survival in adult AMKL is only 10.4 months. [4]

History

TMD was first described and termed congenial leukemia by Bernard and colleagues in a 1951 publication. [19] It was defined to be limited to individuals with Down Syndrome and to be spontaneously regressing in 1954, [20] and thereafter reported to progress to a leukemia in two reports, the first published in 1957 [21] and the second published in 1964. [22] Respective reports by D. Lewis in 1981 [23] and Bennett et al in 1985 [24] indicated that the blast cells involved in TMD and its leukemic sequel were platelet precursor cells. Studies by J.D. Crispino and colleagues in 2002 [25] and 2003 [26] showed that GATA1 mutations were respectively involved in TMD and AMKL.

See also

Related Research Articles

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Megakaryocyte</span> Type of bone marrow cell

A megakaryocyte is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Medical condition

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL gene markers. In PMF, the healthy marrow is replaced by scar tissue (fibrosis), resulting in a lack of production of normal blood cells. Symptoms include anemia, increased infection and an enlarged spleen (splenomegaly).

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Medical condition

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections.

Mean platelet volume (MPV) is a machine-calculated measurement of the average size of platelets found in blood and is typically included in blood tests as part of the CBC. Since the average platelet size is larger when the body is producing increased numbers of platelets, the MPV test results can be used to make inferences about platelet production in bone marrow or platelet destruction problems.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in the species Homo sapiens

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

<span class="mw-page-title-main">PDGFRB</span> Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.

<span class="mw-page-title-main">GATA2</span> Protein-coding gene in the species Homo sapiens

GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Hematologic diseases are disorders which primarily affect the blood & blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease & complications from chemotherapy or transfusions.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

<span class="mw-page-title-main">Emberger syndrome</span> Medical condition

The Emberger syndrome is a rare, autosomal dominant, genetic disorder caused by familial or sporadic inactivating mutations in one of the two parental GATA2 genes. The mutation results in a haploinsufficiency in the levels of the gene's product, the GATA2 transcription factor. This transcription factor is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissues. The syndrome includes as its primary symptoms: serious abnormalities of the blood such as the myelodysplastic syndrome and acute myeloid leukemia; lymphedema of the lower limbs, and sensorineural hearing loss. However, the anomalies caused by GATA2 mutations are highly variable with some individuals showing little or no such symptoms even in old age while others exhibit non-malignant types of hematological anomalies; lymphedema in areas besides the lower limbs, little or no hearing loss; or anomalies in other tissues. The syndrome may present with relatively benign signs and/or symptoms and then progress rapidly or slowly to the myelodysplastic syndrome and/or acute myeloid leukemia. Alternatively, it may present with one of the latter two life-threatening disorders.

GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.

References

  1. 1 2 3 4 5 6 7 8 Tamblyn JA, Norton A, Spurgeon L, Donovan V, Bedford Russell A, Bonnici J, Perkins K, Vyas P, Roberts I, Kilby MD (January 2016). "Prenatal therapy in transient abnormal myelopoiesis: a systematic review". Archives of Disease in Childhood: Fetal and Neonatal Edition. 101 (1): F67–71. doi:10.1136/archdischild-2014-308004. PMID   25956670. S2CID   5958598.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I (October 2016). "Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update". Current Hematologic Malignancy Reports. 11 (5): 333–41. doi:10.1007/s11899-016-0338-x. PMC   5031718 . PMID   27510823.
  3. 1 2 3 Seewald L, Taub JW, Maloney KW, McCabe ER (September 2012). "Acute leukemias in children with Down syndrome". Molecular Genetics and Metabolism. 107 (1–2): 25–30. doi:10.1016/j.ymgme.2012.07.011. PMID   22867885.
  4. 1 2 3 4 5 Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC   5391620 . PMID   28179280.
  5. 1 2 3 4 5 6 Gamis AS, Smith FO (November 2012). "Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder". British Journal of Haematology. 159 (3): 277–87. doi: 10.1111/bjh.12041 . PMID   22966823. S2CID   37593917.
  6. ↑ Traisrisilp K, Charoenkwan P, Tongprasert F, Srisupundit K, Tongsong T (October 2016). "Hemodynamic assessment of hydrops foetalis secondary to transient myeloproliferative disorder associated with foetal Down syndrome: A case report and literature review". Journal of Obstetrics and Gynaecology. 36 (7): 861–864. doi:10.1080/01443615.2016.1174833. PMID   27612526. S2CID   26001927.
  7. 1 2 Marshall GM, Carter DR, Cheung BB, Liu T, Mateos MK, Meyerowitz JG, Weiss WA (April 2014). "The prenatal origins of cancer". Nature Reviews. Cancer. 14 (4): 277–89. doi:10.1038/nrc3679. PMC   4041218 . PMID   24599217.
  8. ↑ Rozen L, Huybrechts S, Dedeken L, Heijmans C, Dessars B, Heimann P, Lambert F, Noubouossie DF, Ferster A, Demulder A (December 2014). "Transient leukemia in a newborn without Down syndrome: case report and review of the literature". European Journal of Pediatrics. 173 (12): 1643–7. doi:10.1007/s00431-013-2163-8. PMID   24253371. S2CID   281098.
  9. 1 2 Shimizu R, Yamamoto M (August 2016). "GATA-related hematologic disorders". Experimental Hematology. 44 (8): 696–705. doi: 10.1016/j.exphem.2016.05.010 . PMID   27235756.
  10. ↑ "GATA1 GATA binding protein 1 [Homo sapiens (human)] - Gene - NCBI".
  11. 1 2 3 4 Fujiwara T (June 2017). "GATA Transcription Factors: Basic Principles and Related Human Disorders". The Tohoku Journal of Experimental Medicine. 242 (2): 83–91. doi: 10.1620/tjem.242.83 . PMID   28566565.
  12. 1 2 Katsumura KR, DeVilbiss AW, Pope NJ, Johnson KD, Bresnick EH (September 2013). "Transcriptional mechanisms underlying hemoglobin synthesis". Cold Spring Harbor Perspectives in Medicine. 3 (9): a015412. doi:10.1101/cshperspect.a015412. PMC   3753722 . PMID   23838521.
  13. ↑ Da Costa L, O'Donohue MF, van Dooijeweert B, Albrecht K, Unal S, Ramenghi U, Leblanc T, Dianzani I, Tamary H, Bartels M, Gleizes PE, Wlodarski M, MacInnes AW (October 2017). "Molecular approaches to diagnose Diamond-Blackfan anemia: The EuroDBA experience". European Journal of Medical Genetics. 61 (11): 664–673. doi: 10.1016/j.ejmg.2017.10.017 . PMID   29081386.
  14. 1 2 3 Gruber TA, Downing JR (August 2015). "The biology of pediatric acute megakaryoblastic leukemia". Blood. 126 (8): 943–9. doi:10.1182/blood-2015-05-567859. PMC   4551356 . PMID   26186939.
  15. ↑ Zipursky A, Brown EJ, Christensen H, Doyle J (March 1999). "Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome". Clinics in Laboratory Medicine. 19 (1): 157–67, vii. doi:10.1016/S0272-2712(18)30133-1. PMID   10403079.
  16. ↑ Verrucci M, Pancrazzi A, Aracil M, Martelli F, Guglielmelli P, Zingariello M, Ghinassi B, D'Amore E, Jimeno J, Vannucchi AM, Migliaccio AR (November 2010). "CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin". Journal of Cellular Physiology. 225 (2): 490–9. doi:10.1002/jcp.22228. PMC   3780594 . PMID   20458749.
  17. ↑ Gilles L, Arslan AD, Marinaccio C, Wen QJ, Arya P, McNulty M, Yang Q, Zhao JC, Konstantinoff K, Lasho T, Pardanani A, Stein B, Plo I, Sundaravel S, Wickrema A, Migliaccio A, Gurbuxani S, Vainchenker W, Platanias LC, Tefferi A, Crispino JD (April 2017). "Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis". The Journal of Clinical Investigation. 127 (4): 1316–1320. doi:10.1172/JCI82905. PMC   5373858 . PMID   28240607.
  18. ↑ Gassmann W, Löffler H (1995). "Acute megakaryoblastic leukemia". Leukemia & Lymphoma. 18 Suppl 1: 69–73. doi:10.3109/10428199509075307. PMID   7496359.
  19. ↑ BERNHARD WG, GORE I, KILBY RA (November 1951). "Congenital leukemia". Blood. 6 (11): 990–1001. doi: 10.1182/blood.V6.11.990.990 . PMID   14869361.
  20. ↑ SCHUNK GJ, LEHMAN WL (May 1954). "Mongolism and congenital leukemia". Journal of the American Medical Association. 155 (3): 250–1. doi:10.1001/jama.1954.73690210004006b. PMID   13151913.
  21. ↑ KRIVIT W, GOOD RA (September 1957). "Simultaneous occurrence of mongolism and leukemia; report of a nationwide survey". AMA Journal of Diseases of Children. 94 (3): 289–93. doi:10.1001/archpedi.1957.04030040075012. PMID   13457660.
  22. ↑ HONDA F, PUNNETT HH, CHARNEY E, MILLER G, THIEDE HA (December 1964). "Serial cytogenetic and hematologic studies on amongol with trisomy-21 and acute congenital leukemia". The Journal of Pediatrics. 65 (6): 880–7. doi:10.1016/S0022-3476(64)80012-3. PMID   14244095.
  23. ↑ Lewis DS (September 1981). "Association between megakaryoblastic leukaemia and Down syndrome". Lancet. 2 (8248): 695. doi:10.1016/s0140-6736(81)91027-8. PMID   6116071. S2CID   1602479.
  24. ↑ Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (September 1985). "Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group". Annals of Internal Medicine. 103 (3): 460–2. doi:10.7326/0003-4819-103-3-460. PMID   2411180.
  25. ↑ Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (September 2002). "Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome". Nature Genetics. 32 (1): 148–52. doi:10.1038/ng955. PMID   12172547. S2CID   5745608.
  26. ↑ Greene ME, Mundschau G, Wechsler J, McDevitt M, Gamis A, Karp J, Gurbuxani S, Arceci R, Crispino JD (2003). "Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome". Blood Cells, Molecules & Diseases. 31 (3): 351–6. doi:10.1016/j.bcmd.2003.08.001. PMID   14636651.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.