Human Disease Model Report: chronic myeloid leukemia, BCR-ABL1 fusions

General Information

Name

chronic myeloid leukemia, BCR-ABL1 fusions

FlyBase ID

FBhh0001049

Disease Ontology Term

chronic myeloid leukemia

Parent Disease

OMIM

LEUKEMIA, CHRONIC MYELOID; CML

Overview

This report describes chronic myeloid leukemia (CML). CML is most frequently caused by a cytogenetic abnormality known as the Philadelphia chromosome, where part of chromosome 22 translocates to chromosome 9. This creates a constitutively active fusion product of the human genes BCR and ABL1, both kinases.

Multiple groups have introduced a BCR-ABL1 fusion gene into flies (Hsap\ABL1::Hsap\BCR, Abl::Hsap\ABL1::Hsap\BCR). Expression of BCR-ABL1 in the eye produces undifferentiated, dysfunctional eyes, and lethality when expressed in the CNS. Expression in the lymph gland (the hematopoietic organ in Drosophila) causes hemocytes to aggregate and form melanotic nodules, a sign of excessive hematopoiesis. Use of the eye phenotypes has allowed screening of CML therapeutic drug candidates and regimens.

A mutation within the ABL1 kinase domain of the fusion protein is associated with resistance to tyrosine kinase inhibitors frequently used in treatment of CML. This mutation, ABL1:p.Thr315Ile , has been introduced into one of the BCR-ABL1 fusion constructs and has been characterized in flies, particularly in terms of mechanisms of drug resistance.

[updated Feb. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: chronic myeloid leukemia, BCR-ABL1 fusions

OMIM report

[LEUKEMIA, CHRONIC MYELOID; CML](https://omim.org/entry/608232)

Human gene(s) implicated

[ABL PROTOONCOGENE 1, NONRECEPTOR TYROSINE KINASE; ABL1](https://omim.org/entry/189980)

[BCR ACTIVATOR OF RhoGEF AND GTPase; BCR](https://omim.org/entry/151410)

Symptoms and phenotype

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B lymphoid, and sometimes T lymphoid cells, but not marrow fibroblasts. [from MIM:608232, 06.07.2019]

(OMIM, 2013-)

Genetics

95% of CML patients have the translocation event which creates the constitutively active protein tyrosine kinase fusion gene BCR-ABL1. (Bernardoni et al. 2018 and references therein, FBrf0241911.)

(FlyBase Curators, 2013-)

Chronic myeloid leukemia is most frequently caused by a translocation between chromosomes 22 and 9, creating a BCR/ABL fusion gene encoding a tyrosine kinase. A distinct feature of disease progression is the appearance of additional cytogenetic abnormalities in the Ph-positive cells. This phenomenon, known as clonal evolution, frequently involves a second Ph, trisomy of chromosome 8, and isochromosome 17 and other abnormalities of chromosome 17 (Kantarjian et al., 1988, pubmed:3162181), although other abnormalities have been described. [from MIM:608232, 06.07.2019]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

External links

COSMIC fusion: BCR-ABL1
Gene2Function (human gene): BCR
Gene2Function (human gene): ABL1
Gene Cards: BCR
Gene Cards: ABL1
MedlinePlus (condition): Chronic myeloid leukemia
MedlinePlus (gene): BCR
MedlinePlus (gene): ABL1
KEGG Disease Pathways: Chronic myeloid leukemia
MARRVEL (human gene): BCR
MARRVEL (human gene): ABL1
NCBI MedGen: Chronic myelogenous leukemia
NCBI (Entrez) gene: BCR; BCR activator of RhoGEF and GTPase
NCBI (Entrez) gene: ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase

Disease synonyms

BCR-ABL

chronic myelogenous leukemia

CML

Related Diseases

Related human health report(s)

cancer, epithelial, ABL-related

hematologic cancer (fly models overview)

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

BCR; BCR activator of RhoGEF and GTPase

D. melanogaster ortholog (based on DIOPT)

Dmel\RhoGAP1A

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: one human gene to one Drosophila gene.

Human gene (HGNC)

Symbol / Name

ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase

D. melanogaster ortholog (based on DIOPT)

Dmel\Abl

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: one human gene to one Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Abl

Gene Snapshot

Abl tyrosine kinase (Abl) encodes a non-receptor tyrosine kinase best known for its ortholog's role in human leukemia. It phosphorylates cell adhesion and cytoskeletal proteins and acts as a scaffold in a signaling complex to regulate both epithelial and nervous system morphogenesis. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

NON-RTK

Comments on ortholog(s)

Single, moderate-ranking ortholog of human ABL1.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\RhoGAP1A

Gene Snapshot

Rho GTPase activating protein at 1A (RhoGAP1A) encodes a protein involved in Golgi organization and cell growth inhibition. [Date last reviewed: 2019-07-11]

Molecular function (GO)

Cellular component (GO)

membrane

Gene Groups / Pathways

Comments on ortholog(s)

Single, high-ranking ortholog of human BCR.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (22 groups)

Abl

protein-protein

Interacting group

Assay

References

Abl

protein kinase assay, autoradiography, enzymatic study

(Lin et al., 2004, Gertler et al., 1995)

Abl - Abi

pull down, western blot, enzymatic study, inferred by author

(Lin et al., 2004, Juang and Hoffmann, 1999)

Abl - capt

anti bait coimmunoprecipitation, western blot, anti tag western blot

(Wills et al., 2002)

Abl - Cdk1

protein kinase assay, autoradiography

(Lin et al., 2004)

Abl - Cyfip

pull down, Identification by mass spectrometry

(Cheong et al., 2020)

Abl - Dab

anti bait coimmunoprecipitation, western blot

(Kannan et al., 2017)

Abl - Dscam1

anti tag coimmunoprecipitation, anti tag western blot

(Sterne et al., 2015)

Abl - dsh

pull down, autoradiography, enzymatic study, anti tag coimmunoprecipitation, anti tag western blot

(Singh et al., 2010)

Abl - Egfr

two hybrid

(Bianco et al., 2007)

Abl - ena

far western blotting, anti tag western blot, pull down, western blot, enzymatic study, autoradiography, peptide massfingerprinting

(Ahern-Djamali et al., 1999, Wills et al., 1999, Ahern-Djamali et al., 1998, Comer et al., 1998, Gertler et al., 1995)

Abl - eya

protein kinase assay, autoradiography

(Xiong et al., 2009)

Abl - fra

pull down, anti tag western blot, anti tag coimmunoprecipitation, western blot

(O'Donnell and Bashaw, 2013, Dorsten et al., 2010, Forsthoefel et al., 2005)

Abl - Hem

pull down, Identification by mass spectrometry

(Cheong et al., 2020)

Abl - Lar

enzymatic study, surface plasmon resonance, pull down, autoradiography, western blot

(Madan et al., 2011, Wills et al., 1999)

Abl - Mical

two hybrid, anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot

(Yoon et al., 2017)

Abl - N

anti bait coimmunoprecipitation, western blot

(Koca et al., 2022)

Abl - Ptp61F

anti tag coimmunoprecipitation, anti tag western blot

(Ku et al., 2009)

Abl - Ptp69D

enzymatic study, autoradiography

(Wills et al., 1999)

Abl - Ptp99A

surface plasmon resonance, enzymatic study

(Madan et al., 2011)

Abl - Pvr

two hybrid

(Bianco et al., 2007)

Abl - robo1

pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot, western blot

(O'Donnell and Bashaw, 2013, Bashaw et al., 2000)

Abl - trio

pull down, anti tag western blot

(Forsthoefel et al., 2005)

Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)

Abl

Models Based on Experimental Evidence ( 0 )

Allele

Disease

Evidence

References

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

Abl^GD1344

ameliorates chronic myeloid leukemia

modeled by Hsap\ABL1::Hsap\BCR^UAS.cBa

(Bernardoni et al., 2019)

Abl¹

ameliorates fragile X syndrome

modeled by Fmr1^Δ50M

(Sterne et al., 2015)

Abl^K417N.UAS

ameliorates chronic myeloid leukemia

modeled by Hsap\ABL1::Hsap\BCR^UAS.cBa

(Bernardoni et al., 2019)

Abl^UAS.cFa

exacerbates chronic myeloid leukemia

modeled by Hsap\ABL1::Hsap\BCR^UAS.cBa

(Bernardoni et al., 2019)

ameliorates Huntington's disease

modeled by Hsap\HTT^{128Q.1-231.UAS}

(Onur et al., 2021)

Hsap\ABL1::Hsap\BCR

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Hsap\ABL1::Hsap\BCR^UAS.cBa

model of chronic myeloid leukemia

CEA

(Bernardoni et al., 2019)

Hsap\ABL1::Hsap\BCR^UAS.p210

model of chronic myeloid leukemia

CEA

(Abubaker et al., 2022, Outa et al., 2020)

Hsap\ABL1::Hsap\BCR^{T315I.UAS.p210}

model of chronic myeloid leukemia

CEA

(Abubaker et al., 2022, Outa et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Hsap\ABL1::Hsap\BCR^UAS.cBa

model of chronic myeloid leukemia

is ameliorated by Abl^GD1344

(Bernardoni et al., 2019)

is ameliorated by Abl^K417N.UAS

(Bernardoni et al., 2019)

is exacerbated by Abl^UAS.cFa

(Bernardoni et al., 2019)

is exacerbated by Dab^GD4886

(Bernardoni et al., 2019)

is ameliorated by Dab^UAS.cUa

(Bernardoni et al., 2019)

is ameliorated by Stat92E^ΔN.UAS

(Bernardoni et al., 2019)

is ameliorated by Stat92E⁰⁶³⁴⁶

(Bernardoni et al., 2019)

is ameliorated by ena²³

(Bernardoni et al., 2019)

is ameliorated by ena^GD8910

(Bernardoni et al., 2019)

is ameliorated by ena^KK107752

(Bernardoni et al., 2019)

is exacerbated by fax^M7

(Bernardoni et al., 2019)

is exacerbated by pros¹⁷

(Bernardoni et al., 2019)

Abl::Hsap\ABL1::Hsap\BCR

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Abl::Hsap\ABL1::Hsap\BCR^P185.UAS

model of chronic myeloid leukemia

CEA

(Fogerty et al., 1999)

Abl::Hsap\ABL1::Hsap\BCR^P210.UAS

model of chronic myeloid leukemia

CEA

(Fogerty et al., 1999)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Abl::Hsap\ABL1::Hsap\BCR^P185.UAS

P{UAS-P185}

Abl::Hsap\ABL1::Hsap\BCR^P210.UAS

P{UAS-P210}

y¹ w^*; P{UAS-P210}31/CyO

Abl::Hsap\ABL1::Hsap\BCR^KR.UAS

P{UAS-Bcr-Abl.KR}

Hsap\ABL1::Hsap\BCR^UAS.cBa

P{UAS-BCR-ABL1}

Hsap\ABL1::Hsap\BCR^KD.UAS

P{UAS-BCR-ABL1.KD}

Hsap\ABL1::Hsap\BCR^UAS.p210

P{UAS-BCR::ABL1.p210}

Hsap\ABL1::Hsap\BCR^{T315I.UAS.p210}

P{UAS-BCR::ABL1.p210.T315I}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

Abl^UAS.cFa

P{UAS-Abl.F}

w^*; P{UAS-Abl.F}2/CyO; TM2/TM6B, Tb¹

Abl^K417N.UAS

P{UAS-Abl.K417N}

P{UAS-Abl.K417N}2; Abl¹ e^*/TM6B, Tb¹

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

y¹ v¹; P{TRiP.JF02960}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.GL00234}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMC05140}attP40

RhoGAP1A^RNAi.UAS.cBa

P{UAS-RhoGAP1A.RNAi.B}

y¹ w^*; P{UAS-RhoGAP1A.RNAi.B}2

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00267}attP2

RhoGAP1A^GD9492

P{GD9492}

w¹¹¹⁸; P{GD9492}v33029

RhoGAP1A^NIG.17960R

P{NIG.17960R}

P{NIG.17960R}1

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Abl^KO

amorphic allele - molecular evidence

CRISPR/Cas9

w^*; Abl^KO/TM3, Sb¹

Abl²

amorphic allele - genetic evidence

Abl²/TM6B, Tb¹

Abl¹

Abl¹ kar¹ red¹ e¹/TM6B, Tb¹

References (14)

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