CellType: B-cell

Organ_System: hematological system

Notes: Headnote: B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy, but it can occur at any age.B-ALL is classified into subgroups based on the stage of neoplasm B-cell differentiation: pre-pre-B ALL (pro-B ALL), common ALL (cALL), and pre-B ALL.The clinical presentation is variable: fever, fatigue, bone pain, arthralgia, headache, vomiting, and alteration of mental status can be observed. Rarely, patients are asymptomatic. B-ALL is diagnosed initially by routine peripheral blood smear examination. Lymphadenopathy, hepatosplenomegaly, and other extramedullary sites of disease are common, with a predilection for the central nervous system and testes involvement. B-ALL cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations. Recurrent cytogenetic abnormalities occur in 80% of children and in 60-70% of adults with B-ALL. The various forms of B-ALL can be differentiated by their gene expression profiles, which are highly associated with specific chromosomal alterations. Signaling description: MLL gene rearrangements occur in approximately two thirds of infantile ALL cases. MLL is a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The MLL fusion gene, MLL-AF4, contains more than 50% of the rearrangements in pediatric B-ALL cases and occurs in only 4-8% of adult B-ALL cases. It activates HOXA7 and thereby drives leukemic progression. Another fusion gene that occurs in B-ALL is TEL-AML, which is frequent in pediatric cases (30%), but is rare in adults. TEL-AML1 induces a B-cell differentiation arrest and promotes self-renewal in B- cell progenitors. Furthermore, the BCR-ABL1 gene rearrangement is relatively rare (3%) in pediatric patients, but is a common (25%) cytogenetic abnormality in adults. BCR-ABL1 activates SRC, LYN, HCK, and FGR kinases leading to the downstream activation of PI3K/Akt. BCR-ABL1 also activates the RAS/MAPK pathway. In addition, the E2A-HLF oncogenic fusion protein promotes progenitor B-cell survival by up-regulating LMO2 expression and activating the apoptotic inhibitor, BCL2. Another fusion gene, E2A-PBX1, enhances the expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of CDKN2A. Deletion of CDKN2A/B is present in 21-36% of pediatric B-ALL and nearly 50% of adult and adolescent B-ALL cases resulting in increased cell proliferation. Deletions and mutations of PAX5, RAG1/2, IKZF1/3, TCF3, BLNK, CREBBP, and LEF1 impair B-cell differentiation, while mutations of RB1 lead to cell cycle progression. In addition, mutations of TP53 lead to apoptosis impairment. In P2RY8-CRLF2 translocation, CRLF1 and JAK2 activating mutations are strongly associated with B-ALL of Down syndrome patients, but these genetic changes are also observed in non-Down syndrome patients at a much lower rate. Outcome effects: The resulting events are block of differentiation and apoptosis, as well as uncontrolled proliferation which all lead to B-ALL progression. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue.

Description: B-cell lymphoblastic leukemia (B-ALL) is a malignant neoplasm derived from B-cell progenitors. B-ALL is most commonly a childhood malignancy but it can occur at any age. Pathway is built manually using published studies.

Tissue: bone marrow

PMID: 22575265

Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-620d64b9-e93b-42a4-ab5b-50f3f36edd38

NodeType: Pathway

CellType: lymphoblast

Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin

PMID: 22730540

PMID: 20807819

Source: Diseases

PMID: 21149616