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HAEM5:B lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusion (view source)

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{{DISPLAYTITLE:B lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusion}}

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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

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}}</blockquote>

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(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see [[Author_Instructions]] and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])

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(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see [[Author_Instructions]] and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])

==Primary Author(s)*==

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==Clinical Features==

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Put your text here and fill in the table (''Instruction: Can include references in the table'')

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Put your text here and fill in the table (''Instruction: Can include references in the table. Do not delete table.'')

{| class="wikitable"

|'''Signs and Symptoms'''

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|EXAMPLE Asymptomatic (incidental finding on complete blood counts)

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|EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

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EXAMPLE B-symptoms (weight loss, fever, night sweats)

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EXAMPLE: B-symptoms (weight loss, fever, night sweats)

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EXAMPLE Fatigue

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EXAMPLE: Fatigue

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EXAMPLE Lymphadenopathy (uncommon)

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EXAMPLE: Lymphadenopathy (uncommon)

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|'''Laboratory Findings'''

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|EXAMPLE Cytopenias

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|EXAMPLE: Cytopenias

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EXAMPLE Lymphocytosis (low level)

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EXAMPLE: Lymphocytosis (low level)

|}

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Clinical Features~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

No unique clinical features that distinguish this entity from other types of B-ALL. Common clinical features of B-ALL include:

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==Immunophenotype==

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{| class="wikitable sortable"

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!Finding!!Marker

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|Positive (universal)||EXAMPLE CD1

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|Positive (universal)||EXAMPLE: CD1

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|Positive (subset)||EXAMPLE CD2

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|Positive (subset)||EXAMPLE: CD2

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|Negative (universal)||EXAMPLE CD3

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|Negative (universal)||EXAMPLE: CD3

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|Negative (subset)||EXAMPLE CD4

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|Negative (subset)||EXAMPLE: CD4

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Immunophenotype~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

Blasts with pre-B phenotype, positive for CD19, CD10 and cytoplasmic mu heavy chain. <ref name=":1" />

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!Notes

|-

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|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

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|EXAMPLE: t(9;22)(q34;q11.2)||EXAMPLE: 3'ABL1 / 5'BCR||EXAMPLE: der(22)||EXAMPLE: 20% (COSMIC)

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EXAMPLE 30% (add reference)

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EXAMPLE: 30% (add reference)

|Yes

|No

|Yes

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|EXAMPLE

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|EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Chromosomal Rearrangements (Gene Fusions)~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

The breakpoints of the t(1;19) translocation typically fall within intron 16 of ''TCF3'' and intron 3 of ''PBX1''. <ref name=":0" />

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).~~|Please incorporate this section into the relevant tables found in:

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Please incorporate this section into the relevant tables found in:

* Chromosomal Rearrangements (Gene Fusions)

* Individual Region Genomic Gain/Loss/LOH

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==Individual Region Genomic Gain / Loss / LOH==

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Put your text here and fill in the table (''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'')

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Put your text here and fill in the table (''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'')

{| class="wikitable sortable"

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!Notes

|-

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|EXAMPLE

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|EXAMPLE:

7

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|EXAMPLE Loss

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|EXAMPLE: Loss

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|EXAMPLE

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|EXAMPLE:

chr7:1- 159,335,973 [hg38]

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|EXAMPLE

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|EXAMPLE:

chr7

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|Yes

|No

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|EXAMPLE

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|EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

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|EXAMPLE

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|EXAMPLE:

8

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|EXAMPLE Gain

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|EXAMPLE: Gain

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|EXAMPLE

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|EXAMPLE:

chr8:1-145,138,636 [hg38]

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|EXAMPLE

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|EXAMPLE:

chr8

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|No

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|EXAMPLE

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|EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Genomic Gain/Loss/LOH~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

Secondary somatic copy number aberrations are not frequently seen in ''TCF3-PBX1'' B-ALL

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==Characteristic Chromosomal Patterns==

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Put your text here (''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')

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Put your text here (''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.'')

{| class="wikitable sortable"

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!Notes

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|EXAMPLE

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|EXAMPLE:

Co-deletion of 1p and 18q

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|No

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|EXAMPLE:

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|EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Characteristic Chromosomal Aberrations / Patterns~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

The t(1;19) translocation can be balanced or unbalanced. The unbalanced form has a der(19) resulting in trisomy of 1q distal to PBX1.<ref name=":2">Meloni-Ehrig A., (2013). The principles of clinical cytogenetics. 3rd edition. Steven L. Gersen and Martha B. Keagle , Editors. Springer. DOI 10.1007/978-1-4419-1688-4. p327-329.</ref>

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==Gene Mutations (SNV / INDEL)==

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Put your text here and fill in the table (''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'')

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Put your text here and fill in the table (''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'')

{| class="wikitable sortable"

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!Notes

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|EXAMPLE: TP53; Variable LOF mutations

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|EXAMPLE: TP53; Variable LOF mutations

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EXAMPLE:

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EXAMPLE:

EGFR; Exon 20 mutations

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EXAMPLE: BRAF; Activating mutations

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EXAMPLE: BRAF; Activating mutations

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|EXAMPLE: TSG

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|EXAMPLE: TSG

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|EXAMPLE: 20% (COSMIC)

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|EXAMPLE: 20% (COSMIC)

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EXAMPLE: 30% (add Reference)

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EXAMPLE: 30% (add Reference)

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|EXAMPLE: IDH1 R123H

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|EXAMPLE: IDH1 R123H

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|EXAMPLE: EGFR amplification

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|EXAMPLE: EGFR amplification

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|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

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|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Gene Mutations (SNV/INDEL)~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

Secondary somatic DNA mutations are not frequently seen in ''TCF3-PBX1'' B-ALL. <ref name=":0" />

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==Genes and Main Pathways Involved==

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{| class="wikitable sortable"

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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

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|EXAMPLE: BRAF and MAP2K1; Activating mutations

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|EXAMPLE: BRAF and MAP2K1; Activating mutations

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|EXAMPLE: MAPK signaling

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|EXAMPLE: MAPK signaling

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|EXAMPLE: Increased cell growth and proliferation

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|EXAMPLE: Increased cell growth and proliferation

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|EXAMPLE: CDKN2A; Inactivating mutations

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|EXAMPLE: CDKN2A; Inactivating mutations

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|EXAMPLE: Cell cycle regulation

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|EXAMPLE: Cell cycle regulation

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|EXAMPLE: Unregulated cell division

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|EXAMPLE: Unregulated cell division

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|EXAMPLE: KMT2C and ARID1A; Inactivating mutations

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|EXAMPLE: KMT2C and ARID1A; Inactivating mutations

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|EXAMPLE: Histone modification, chromatin remodeling

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|EXAMPLE: Histone modification, chromatin remodeling

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|EXAMPLE: Abnormal gene expression program

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|EXAMPLE: Abnormal gene expression program

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<blockquote class='blockedit'>{{Box-round|title=~~v4:Genes and Main Pathways Involved~~|~~The content below was from the old template. Please incorporate above.~~}}

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification}}

''TCF3'' gene at 19p13.3 is important during early lymphocyte development, whereas ''PBX1'' at 1q23 is a component of a transcriptional complex that regulates embryogenesis and hematopoiesis. Fusion protein resulting from the TCF3-PBX1 translocation is a transcriptional activator which likely interferes with the normal function of these genes. Expression of this fusion protein is thought to interfere with key regulatory pathways such as WNT and apoptosis/cell cycle control pathways which may drive a leukemic process. The DNA-binding and protein dimerization domains of PBX1 replaces the TCF3 helix-loop-helix DNA-binding motif in ''TCF3-PBX1'' fusion. The remaining transcriptional activating domains of TCF3 leads to constitutive nuclear localization and transformation of PBX1 into an oncogenic transcriptional factor <ref>{{Cite journal|last=Diakos|first=Christofer|last2=Xiao|first2=Yuanyuan|last3=Zheng|first3=Shichun|last4=Kager|first4=Leo|last5=Dworzak|first5=Michael|last6=Wiemels|first6=Joseph L.|date=2014|title=Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein|url=https://pubmed.ncbi.nlm.nih.gov/24503810|journal=PloS One|volume=9|issue=2|pages=e87602|doi=10.1371/journal.pone.0087602|issn=1932-6203|pmc=3913655|pmid=24503810}}</ref><ref name=":1" /><ref name=":0" />

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