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Acute lymphoblastic leukemia in Down syndrome

Written2017-06Karen M. Chisholm
Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA;

Abstract Review on acute lymphoblastic leukemia in Down syndrome, with data on clinics, pathology, and involved genes.

Keywords Down syndrome; leukemia; lymphoblastic leukemia.

(Note : for Links provided by Atlas : click)


ICD-Topo C420,C421,C424
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1784

Clinics and Pathology

Disease Acute lymphoblastic leukemia (ALL) associated with Down syndrome (ALL-DS), is predominantly a B lymphoblastic leukemia, with only very rare cases of mature B cell ALL ( Burkitt leukemia) and T-cell ALL.
Epidemiology Trisomy 21 has an incidence of approximately 1 in 700 live births. The frequency of acute lymphoblastic leukemia in Down syndrome (ALL-DS) is estimated at 1 in 300 (Lange, 2000). The incidence of ALL-DS <5 years of age is 40.7 times greater than that in individuals without Down syndrome of the same age; in addition, there remains an increased risk of ALL-DS compared to those without Down syndrome up to the age of 30 years (Hasle et al., 2000). However, unlike those without Down syndrome, ALL -DS usually does not present in patients <1 year of age.
Clinics Other than the lack of presentation in children <1 year of age, ALL-DS has similar clinical features to ALL in children without Down syndrome, including age, sex, presenting white blood cell count, and NCI risk group (Maloney et al., 2010). Some studies identify similar rates of mediastinal masses and central nervous system involvement at diagnosis in those with ALL-DS and those with ALL without Down syndrome, but other studies identified decreased CNS disease and mediastinal masses in those with ALL-DS (Maloney, 2011).
Cytology Blasts are characterized as small to medium in size with high nuclear-to-cytoplasmic ratios, round to irregular nuclei, smooth chromatin, and scant deeply basophilic agranular cytoplasm.
Figure 1: Bone marrow aspirate smears reveal increased blasts which are small to medium in size with high nuclear-to-cytoplasmic ratios, round to irregular nuclei, smooth chromatin, and scant basophilic agranular cytoplasm. Some background maturing myeloid cells are also present in this case.
Pathology The blasts of ALL-DS usually have an immature B cell phenotype, expressing CD19, CD10, and CD79a.
Cytogenetics The cytogenetics of ALL-DS differs from the cytogenetics in those with ALL not associated with Down syndrome. The children with ALL-DS have a decreased frequency of favorable cytogenetics including high hyperdiploidy, trisomies of chromosomes 4, 10, and 17, and the t(12;21) translocation compared to children without Down syndrome (Maloney et al., 2010; Bruwier and Chantrain, 2012); these ALL-DS children also have a decreased frequency of unfavorable translocations such as t(9;22) and 11q23 (MLL) rearrangements. Overall, these common B-ALL gene rearrangements, which occur at a rate of approximately 60% in non-Down syndrome patients, only occur at a rate of approximately 20% in ALL-DS. Instead, ALL-DS is more likely to have a normal karyotype (with the exception of the constitutional trisomy 21). In those without normal karyotypes, DS-ALL are more likely to be low hyperdiploid, with common acquired changes including +X and/or del(9p) (Forestier et al., 2008; Lundin et al., 2014).
Approximately 50-60% of ALL-DS have been found to have CRLF2 gene rearrangements by FISH or RT-PCR (Mullighan et al., 2009; Hertzberg et al., 2010). The most common rearrangement is a deletion in the pseudoautosomal region 1 (PAR1) of Xp22.33/Yp11 resulting in a fusion between the first noncoding exon on P2RY8 with the entire coding region of CRLF2 ( del(X)(p22.33p22.33)/del(Y)(p11p11)) (Mullighan et al., 2009). Less commonly, CRLF2 rearrangements with IGH (immunoglobulin heavy chain locus) are identified (t(X;14)(p22;q32)/t(Y;14)(p11;q32)). These fusions result in overexpression of CRLF2. Overexpression of CRFL2 has not been found to be correlated with outcome.
Genes JAK2 activating mutations have been found in approximately 20% of ALL-DS, with the most common mutations occurring at or around amino acid R683 in the pseudokinase domain (Bercovich et al., 2008; Kearney et al., 2009; Gaikwad et al., 2009); however, other JAK2 mutations have been identified in ALL-DS, as have mutation in other JAK genes including JAK1 (Mullighan et al., 2009). These JAK2 mutations are found predominantly in those with CRLF2 gene rearrangements. JAK2 mutation status has not been found to correlate with outcome. The JAK2 mutations are thought to act in concert with the CRFL2 gene rearrangements, resulting in cytokine-independent growth and leukemogenesis (Mullighan et al., 2009).
In addition to mutations in the JAK-STAT pathway, mutations in the RAS/receptor tyrosine kinase (RTK) pathway genes such as KRAS and NRAS have been identified at a rate of approximately 35%; these mutations are mutually exclusive of the JAK2 mutations (Nikolaev et al., 2014). However, similar to the JAK2 mutations, the RAS pathway mutations often occur in the setting of CRLF2 rearrangements. Nikolaev et al. (2014) also identified mutations in cohesion complex genes, epigenetic modifiers/remodellers of DNA or chromatin, classical tumor suppressor genes, and lymphoid differentiation factors/markers.
Activating mutations in CRLF2 can also occur, again usually in the setting of CRLF2 gene rearrangements (Hertzberg et al., 2010).
Deletions in IKZF1 are also often found in DS-ALL, estimated at 24-35% (Hertzberg et al., 2010; Buitenkamp et al., 2012), as are deletions in the PAX5 gene (12-22%) (Kearney et al., 2009; Lundin et al., 2012; Buitenkamp et al., 2012). Patients with an IKZF1 deletion or a PAX5 deletion have decreased overall survival compared to those without these deletions (Buitenkamp et al., 2012).
Treatment ALL-DS is treated similarly to ALL in those without Down syndrome. However, some additional modifications and supportive care guidelines are often employed in their treatment, including the use of discontinuous dexamethasone during delayed intensification and adding leucovorin rescue after intrathecal methotrexate (Maloney, 2011). Down syndrome patients have increased susceptibility to methotrexate, with higher rates of mucositis, gastrointestinal toxicity, and hepatotoxicity. Some trials have decreased the methotrexate dosage, increasing the dose only if tolerated. Additionally, Down syndrome patient have a higher risk of hyperglycemia after corticosteroids and asparaginase therapy due to alterations in glucose metabolism.
Prognosis In some studies, children with ALL-DS have been found to have poorer outcomes than children with ALL without Down syndrome, sometimes demonstrating increased induction failures, higher relapse rates, and increased therapy-related mortality. The poorer outcomes are thought to be due, at least in part, to increased sensitivity to methotrexate side effects, and increased susceptibility to infection. The latter susceptibilities are thought to be enhanced by the inherent immunodeficiencies of Down syndrome. However, more recently, with appropriate prognostic group identification based upon favorable and unfavorable cytogenetic features, ALL-DS has been found to have comparable outcomes to ALL not associated with Down syndrome (Maloney et al., 2010; Maloney, 2011). In addition, Buitenkamp et al., 2014 found favorable prognostic factors to include diagnosis < 6 years of age and a WBC <10 x 109/L.
In those who relapse, ALL-DS has a lower event-free survival and lower overall survival compared to those with ALL without Down syndrome, usually due to induction deaths and treatment-related mortality (Meyr et al., 2013). These relapses usually occur late (more than 6 months after completion of therapy) (Meyr et al., 2013; Buitenkamp et al., 2014).
In those who undergo a hematopoietic cell transplant (HCT), post-transplant relapse often occurs, with a probability of 54% within 3 years in one cohort, with an overall survival at 3 years of 29% (Hitzler et al., 2014).

Genes involved and Proteins

Gene NameJAK2 (janus kinase 2)
Location 9p24.1
Protein Protein tyrosine kinase involved in cytokine receptor signaling pathways.
Somatic mutations Mutations often occur in the pseudokinase domain at or around R683 in exon 16 and result in constitutive kinase activity.
Gene NameIKZF1 (Ikaros family zinc finger 1)
Location 7p12.2
Protein Zinc-finger DNA-binding protein that is a transcription factor associated with chromatin remodeling. It is a transcription regulator of lymphocyte differentiation.
Somatic mutations Usually deletions.
Gene NamePAX5 (paired box gene 5)
Location 9p13.2
Protein Paired box transcription factor which has a role in B-cell differentiation, involving regulation of CD19.
Somatic mutations Usually deletions.
Gene NameKRAS (Kirsten rat sarcoma 2 viral oncogene homolog)
Location 12p12.1
Protein RAS oncogene that is a member of the small GTPase family.
Gene NameNRAS (neuroblastoma RAS viral oncogene homolog)
Location 1p13.2
Protein RAS oncogene that is a member of the small GTPase family.
Gene NameCRLF2 (cytokine receptor-like factor 2)
Location Xp22.33
Protein Encodes cytokine receptor-like factor 2 which is a lymphoid signaling receptor that dimerizes with interleukin-7 receptor ( IL7R) to form a receptor for thymic stromal lymphopoietin ( TSLP). This complex (CRLF2/IL7R/TSLP) can stimulate cell proliferation through activation of STAT3 and STAT5.
Somatic mutations Most commonly, translocations occur with P2RY8 or IGH. In addition to the translocations, in some patients activating mutations in CRLF2 can also occur.
Gene NameP2RY8 (purinergic receptor P2Y, G-protein coupled, 8)
Location Xp22.33
Protein Encodes a G-protein coupled purinergic receptor (P2Y, G-protein coupled, 8).
Somatic mutations Through an interstitial deletion, the first noncoding exon of this gene hybridizes with the coding region of CRLF2.
Gene NameIGH (Immunoglobulin Heavy)
Location 14q32.33
Protein Immunoglobulin heavy chain.
Somatic mutations Through a translocation, this gene hybridizes to CRLF2.

Result of the chromosomal anomaly

Hybrid gene
Note The P2RY8/CRLF2 fusion is much more common than the IGH/CRLF2 fusion.
Description An interstitial deletion in the pseudoautosomal region 1 (PAR1) of Xp22.3/Yp11 occurs in the P2RY8/CRLF2 fusion, hybridizing the first noncoding exon of P2RY8 to the entire coding region of CRLF2 [del(X)(p22.33p22.33)/del(Y)(p11.32p11.32)]. Alternatively, a translocation occurs between CRLF2 and IGH resulting in t(X;14)(p22;q32)/t(Y;14)(p11;q32).
Detection These fusions can be detected by FISH or RT-PCR.
Fusion Protein
Oncogenesis Results in overexpression/dysregulated expression of CRLF2.


Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome
Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, Shochat C, Cazzaniga G, Biondi A, Basso G, Cario G, Schrappe M, Stanulla M, Strehl S, Haas OA, Mann G, Binder V, Borkhardt A, Kempski H, Trka J, Bielorei B, Avigad S, Stark B, Smith O, Dastugue N, Bourquin JP, Tal NB, Green AR, Izraeli S
Lancet. 2008 Oct 25;372(9648):1484-92.
PMID 18805579
Hematological disorders and leukemia in children with Down syndrome.
Bruwier A, Chantrain CF
Eur J Pediatr. 2012 Sep;171(9):1301-7
PMID 22113227
Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations
Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JP, Beverloo HB, Zimmermann M, de Haas V, Richards SM, Vora AJ, Mitchell CD, Russell LJ, Schwab C, Harrison CJ, Moorman AV, van den Heuvel-Eibrink MM, den Boer ML, Zwaan CM
Leukemia. 2012 Oct;26(10):2204-11.
PMID 22441210
Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study.
Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalová K, Stark B, Harrison CJ, Teigler-Schlegel A, Johansson B
Blood. 2008 Feb 1;111(3):1575-83
PMID 17971484
Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia
Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, Plon SE, Basso G, Pession A, Rabin KR
Br J Haematol. 2009 Mar;144(6):930-2
PMID 19120350
Risks of leukaemia and solid tumours in individuals with Down's syndrome
Hasle H, Clemmensen IH, Mikkelsen M.
Lancet. 2000 Jan 15;355(9199):165-9
PMID 10675114
Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group
Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S
Blood. 2010 Feb 4;115(5):1006-17.
PMID 19965641
Outcome of transplantation for acute lymphoblastic leukemia in children with Down syndrome
Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan KW, Diaz Perez MA, Fraser C, Gross TG, Horan JT, Kennedy-Nasser AA, Kitko C, Kurtzberg J, Lehmann L, O'Brien T, Pulsipher MA, Smith FO, Zhang MJ, Eapen M, Carpenter PA; CIBMTR Pediatric Cancer Working Committee
Pediatr Blood Cancer. 2014 Jun;61(6):1126-8
PMID 24391118
Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia
Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M, Bateman CM, Anderson K, Chaplin T, Young BD, Harrison CJ, Kempski H, So CW, Ford AM, Greaves M
Blood. 2009 Jan 15;113(3):646-8.
PMID 18927438
The management of neoplastic disorders of haematopoiesis in children with Down's syndrome
Lange B.
Br J Haematol. 2000 Sep;110(3):512-24.
PMID 10997960
Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries
Lundin C, Forestier E, Klarskov Andersen M, Autio K, Barbany G, Cavelier L, Golovleva I, Heim S, Heinonen K, Hovland R, Johannsson JH, Kjeldsen E, Nordgren A, Palmqvist L, Johansson B; Nordic Society of Pediatric Hematology Oncology (NOPHO); Swedish Cytogenetic Leukemia Study Group (SCLSG); NOPHO Leukemia Cytogenetic Study Group (NLCSG)
J Hematol Oncol. 2014 Apr 11;7:32
PMID 24726034
High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
Lundin C, Hjorth L, Behrendtz M, Nordgren A, Palmqvist L, Andersen MK, Biloglav A, Forestier E, Paulsson K, Johansson B
Genes Chromosomes Cancer. 2012 Feb;51(2):196-206
PMID 22072402
Acute lymphoblastic leukaemia in children with Down syndrome: an updated review
Maloney KW
Br J Haematol. 2011 Nov;155(4):420-5.
PMID 21933171
Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group.
Maloney KW, Carroll WL, Carroll AJ, Devidas M, Borowitz MJ, Martin PL, Pullen J, Whitlock JA, Willman CL, Winick NJ, Camitta BM, Hunger SP.
Blood. 2010 Aug 19;116(7):1045-50.
PMID 20442364
Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome
Meyr F, Escherich G, Mann G, Klingebiel T, Kulozik A, Rossig C, Schrappe M, Henze G, von Stackelberg A, Hitzler J
Br J Haematol. 2013 Jul;162(1):98-106
PMID 23594030
Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia
Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, Ma J, Coustan-Smith E, Harvey RC, Willman CL, Mikhail FM, Meyer J, Carroll AJ, Williams RT, Cheng J, Heerema NA, Basso G, Pession A, Pui CH, Raimondi SC, Hunger SP, Downing JR, Carroll WL, Rabin KR
Nat Genet. 2009 Nov;41(11):1243-6
PMID 19838194
Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
Nikolaev SI, Garieri M, Santoni F, Falconnet E, Ribaux P, Guipponi M, Murray A, Groet J, Giarin E, Basso G, Nizetic D, Antonarakis SE
Nat Commun. 2014 Aug 8;5:4654
PMID 25105841


This paper should be referenced as such :
Karen M Chisholm
Acute lymphoblastic leukemia in Down syndrome
Atlas Genet Cytogenet Oncol Haematol. 2018;22(8):341-345.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes CRLF2

External links

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