Acute biphenotypic leukemia
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Biphenotypic acute leukaemia (BAL) is an uncommon type of leukemia which arises in multipotent progenitor cells which have the ability to differentiate into both
myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
and
lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
lineages. It is a subtype of "leukemia of ambiguous lineage". The direct reasons leading to BAL are still not clear. BAL can be de novo or secondary to previous cytotoxic therapy. Many factors, such viruses,
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...
factors, and
radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...
, might have a relationship with BAL. BAL is hard to treat. Usually the
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
is chosen according to the morphology of the blast (
ALL All or ALL may refer to: Language * All, an indefinite pronoun in English * All, one of the English determiners * Allar language (ISO 639-3 code) * Allative case (abbreviated ALL) Music * All (band), an American punk rock band * ''All'' (All al ...
or AML). A blood-forming stem-cell transplantation is highly recommended. About 5% of acute leukaemia cases are BAL. BAL can occur in all ages of people but occurs more in adults than in children.


Signs and symptoms

BAL has similar symptoms to other types of leukemia, but they are usually more serious. Symptoms caused by bone marrow damage
Bruising A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur close e ...
, spotting: the reason is lack of platelets. it is very common in BAL patients, most of patients die due to the A low level of red blood cells in the bloodstream: Because the decline of hematopoietic function, need blood transfusion therapy Persistent fever, infection prolonged healing: Diffuse hemorrhage: which is dangerous and might lead to death. Symptoms caused by blood cancer cells infiltration into tissues:
Swollen lymph nodes Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
Joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...
Swelling of the gums Enlargement of the liver and spleen Headache and
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
: blood cancer infiltration into the wear performance of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. Skin lumps: Because look was slightly green, also known as the "Green tumor." Pericardial or
pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilog ...


Causes

The cause that directly leads to BAL is unclear. Exposure to
radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...
, chemical exposure, virus and
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
are the primary reasons proposed by researchers.


Mechanisms

The mechanism of BAL is related to several mutations. The most common abnormalities are t(9;22) and MLL
gene rearrangement V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell rece ...
at 11q23. T(9;22) affect the ABL gene at 9q34 and BCR at 22q11. The hybrid gene product ABL/BCR is an oncogene which could lead several types of leukemia including BAL. ABL/BCR could active several molecular pathways: # RAS signaling could be activated by BCR/ABL by GRB2 adaptor which interact with Y177 of BCR. # Through AKT/PKB, PI3-K pathway could also be activated. #
STAT5 Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the prote ...
, 1, and 6 has been reported that is a major molecular signaling event activated by BCR/ABL. # Some focal adhesion complex (PAXILLIN, FAK0 could be activated by BCR/ABL with adaptor molecule CRK-L. # BCR/ABL could inactivate negative regulatory molecules PTP1B and Abi-1. Their inactivation is related with progression into blast crisis. # BCR/ABL pathway could also active PI64K/Akt/STAT5 pathway which has anti-apoptotic activity. # BCR/ABL induce cell adhesive and migratory abnormalities because the mutation will lead an abnormal response to chemokine SDF-1 MLL gene encode Histone-lysine N-methyltransferase (HRX), which is a
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
methyltransferase. It is a positive regulator for gene transcription. It has been shown that associates with Host cell factor C1,
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
binding protein,
WDR5 WD repeat-containing protein 5 is a protein that in humans is encoded by the ''WDR5'' gene. This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed ...
, CTBP,
MEN1 Menin is a protein that in humans is encoded by the ''MEN1'' gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome). ''In vitro'' studies have shown that menin is localized to the nucleus, ...
, etc. The rearrangement of MLL are related with different kinds of aggressive acute leukemias. Most of biphenotypic leukemia in children is due to the rearrangement of MLL Besides them, other gene abnormalities has been reported. Such as t(8;21), t(15;17), del(6q), del(12p), t(x;12) and t(14;19). In BAL patients, it is prone to
bruising A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur close e ...
, spotting, which is due to megakaryocytes that could produce platelets decrease, resulting in a lack of platelets. Anemia: reduction metrocytes that could produce red blood cells, resulting in a lack of red blood cells. Patients are prone to asthma and dizziness in walking or exercise. Persistent fever, infection prolonged healing: Most of the white blood cells are leukemia cells, no normal function, leading to decreased immunity, susceptible to infection.


Diagnosis

Following observation of the symptoms, the patients need to get complete
blood counts A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and plat ...
and a
bone marrow examination Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of condition ...
. If the patient has leukemia, the morphology and immunophenotype check is needed to make sure the type of leukemia. The
morphology Morphology, from the Greek and meaning "study of shape", may refer to: Disciplines *Morphology (archaeology), study of the shapes or forms of artifacts *Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
of the blast in BAL is not certain. The cells could display both myeloid lineage and lymphoid or undifferentiated morphology. Therefore, the diagnosis cannot based on the morphology result. The immunophenotype check is the most important basis of the diagnosis of BAL. Before 2008, the diagnosis of BAL was based on a score system proposed by the European Group for the Immunological Classification of Leukemias (EGIL) which could differentiate from other kinds of acute leukemia. The table shows this method. If the score of only one lineage is higher than 2, the acute leukemia could be acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). According to the original EGIL scoring system BAL is defined when scores are over two points for both myeloid and T- or B- lymphoid lineages. In 2008,
WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book ''Horton Hear ...
established a new and strict criteria standard for diagnosis of BAL. The presence of specific T-lymphoid antigens, cytoplasmic CD3 (cCD3), MPO and CD 19 became the most important standard for recognizing the lineage. Other B-lineage markers (CD22, CD79a, CD 10) and monocytic markers are also needed. Table 2 shows the method. Compared with the EGIL scoring system, the current 2008 WHO criteria applied less but more specific markers to define the lineage of the blasts, and incorporated the intensity of markers expression into the diagnostic algorithm. The diagnosis of BAL is so difficult that sometimes is misdiagnosed with AML or ALL because the morphology thus the therapy would not have a good effect.


Treatment

BAL is difficult to treat, most patients receive treatment based on the morphology of blasts and get AML or ALL induction chemotherapy. The induction drug for AML such as
cytarabine Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by in ...
and
anthracycline Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cance ...
, drug for ALL such as
prednisolone Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthrit ...
,
dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...
,
vincristine Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's ...
,
asparaginase Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). It is given by injection into a vein, muscl ...
or
daunorubicin Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. It ...
is common for BAL remission induction therapy. Recently, researches showed that using both
myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
and
lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
induction therapy may be better for prognosis.
Chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
has strong
side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
such as
typhlitis Neutropenic enterocolitis is inflammation of the cecum (part of the large intestine) that may be associated with infection. It is particularly associated with neutropenia, a low level of neutrophil, neutrophil granulocytes (the most common form of ...
, gastrointestinal distress, anemia, fatigue,
hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and vomiting, etc. Thus, the different dose and times of chemotherapy for different individuals is important. If the patients enter fully remission, the consolidation with
stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
is highly recommended.


Prognosis

The prognosis for BAL patients is not good which is worse than ALL and AML. Medical Blood Institute reported cases of CR rate was 31.6%, with a median remission are less than 6 months The median survival time is only 7.5 months. The life quality is also low because the immune function of patient is damaged seriously. They have to stay in hospital and need 24h care. In another study, the results showed that young age, normal
karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
and ALL induction therapy will have a better prognosis than Ph+, adult patients. The study shows median survival of children is 139 months versus 11 months of adults, 139 months for normal karyotype patients versus 8 months for ph+ patients.


Recent research

Research on the mechanisms of BAL does not show a great progress in terms of the causes, molecular processes and therapy. Some new translocate case of BAL has been reported, such as t(15,17) and t(12,13). For t(15;17), the blasts with morphology of acute lymphoblastic leukemia co-expressed in B-lymphoid and myeloid lineages, and the cytogenetic study showed that the 4q21 abnormalities and t(15;17). However, promyelocytic-retinoid acid receptor rearrangement was not found by fluorescence in situ hybridization on interphase nuclei. Researchers also found some new chemotherapy method for specific cases. For example, The chemotherapy for ALL and gemtuzuab ozogamicin without all-trans-retinoic acid remain complete remission of the BAL patients with t(15,17) for more than 3.7 years. The detection of BCR-ABL1 chimeric gene neutrophils was also found a good method for diagnosis some cases of BAL.


References


External links

{{Myeloid malignancy Anatomical pathology Acute lymphocytic leukemia Acute myeloid leukemia