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del(9p) in Acute Lymphoblastic Leukemia

Written2016-09Anwar N. Mohamed
Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA.

Abstract Review on del(9p) in acute lymphoblastic leukemia, with data on clinics, and the genes involved.

Keywords chromosome 9; del(9p); acute lymphoblastic leukemia

(Note : for Links provided by Atlas : click)


ICD-Topo C420,C421,C424
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
Atlas_Id 1064
Note Deletion of 9p is a common recurring chromosomal aberration in acute lymphoblastic leukemia (ALL) of both B- and T-lineages ALL. The 9p region contains numerous cancer-associated genes such as JAK2, CD274 (PDL1)/ PDCD1LG2 (PDL2) at 9p24.1, CDKN2A, CDKN2B, MTAP, IFN, MLLT3, and HACD4 (PTPLAD2) at 9p21.3 as well as PAX5 at 9p13.2. Several of these genes have been implicated in the leukemogenesis of ALL (Mullighan CG 2012, Harrison CJ 2013).

Clinics and Pathology

Disease Acute lymphoblastic leukemia (ALL)
Epidemiology Visible deletions of 9p by karyotype are seen in approximately 10% of ALL cases of both children (7-11%) and adult (5-15%). The loss of 9p is the second most frequent abnormality after t(9;22)/Ph in adult ALL, and the third after high hyperdiploidy and t(12;21) inpediatric ALL (Moorman et al 2010). The minimal commonly deleted segment is band 9p21 encompassing the tumor suppressor genes CDKN2A and CDKN2B.
Clinics At diagnosis patients are likely to have higher WBC counts, older age, male gender, splenomegaly, and hypodiploid karyotype than patients lacking 9p deletions (Heerema et al 1999). In addition, patients with a 9p abnormality have an increasing incidence of both marrow and central nervous system relapses.
Prognosis The prognostic significance of 9p21/CDKN2A deletion has remained indecisive particularly in pediatric B-ALL. The differences in patient population and study designs among different studies may have had an impact on the overall results.
In Pediatric B-ALL Initial studies on a small number of patients suggested that deletion of 9p/CDKN2A was associated with an increased risk of relapse and death although other report concluded no prognostic effect on the disease outcome (Kees et al 1997, Zhou et al 1997). On a large cohort study, Heerema et al showed a high frequency of 9p abnormalities in ALL patients with high-risk or lymphomatous features, and an overall poorer outcome compared with those lacking this abnormality. Their data also indicated that 9p abnormalities identify a subgroup of NCI standard-risk patients with increased risk of treatment failure.
Yet, the recent study by Sulong et al concluded that CDKN2A deletion is a significant secondary genetic abnormality and variation in the incidence of CDKN2A deletion among the cytogenetic subgroups may explain its inconsistent association with outcome. Conversely, the dicentric (9;12) has been associated with a favorable outcome in pediatric ALL.
In Adult B-ALL Patients with 9p deletions have significantly shorter overall survival when compared with patients with normal karyotypes. The overall survival is similar to that in the poor prognosis t(9;22 )/ BCR/ ABL1-positive group (Nahi et al 2008).
In T-ALL The prognostic implications of loss of heterozygosity (LOH) of 9p were evaluated in pediatric T-ALL patients treated uniformly according to the Berlin-Frankfurt-Munster regimen. This study showed that LOH of 9p was associated with a favorable initial treatment response, and the event free survival was slightly favorable (Krieger et al 2010).


Cytogenetics Morphological The loss of material from 9p can result from a simple deletion in approximately 40% of cases or from various unbalanced translocations giving rise to a partial or complete loss of 9p such as isochromsome i(9)(q10), dicentric dic(9;12) and dic(9;20), whole arm der(V;9q10), and add(9p) [Figure 1]. The majority of 9p deletions are associated with a nonhyperdiploid karyotype (Heerema et al 1999). Although deletion of 9p occurs as a sole abnormality in ~20% of cases, it is frequently accompanied by other primary genetic abnormalities such as t(1;19)(q23;p13.3), t(9;22)(q34;q11.2), t(12;21)(p13;q22), t(14q32) and inv(14)(q11.2q32) suggesting that 9p deletion is a secondary change.
Deletions of 9p often are not easily detected by G-banding. Therefore, FISH testing targeting the CDKN2A gene provides an excellent method for detecting the majority of these deletions. In large series studies, the frequency of CDKN2A/B deletions has been reported in 20%-34% of B- ALL but is significantly higher among T-ALL patients 50%-80%. The distribution of 9p deletion among the cytogenetic subgroups varies. Patients with t(9;22) and t(1;19) have higher incidences of CDKN2A/B deletion (40%-60%) than patients with high hyperdiploidy, ETV6/ RUNX1 fusion , or KMT2A (MLL)/11q23 rearrangements (11%-15%). Both monoallelic and biallelic CDKN2A deletions are found in ALL with the latter being more prevalent in T-ALL (Sulong et al, 2009). The deletions vary in size considerably from <1 Mb to 39 Mb, and the biallelic deletions consist of a large and small deletion. In contrast, inactivation of CDKN2A gene in ALL by mutation or hypermethylation appears to be low, ranging from 0-7%.
  Figure 1; Top: Partial G-banded karyotype showing partial deletion 9p, der(9;16)(q10;p10), i(9(q10) [left to right]. Bottom: FISH on metaphase cell (left) and interphase cell (right) showing one copy of CDKN2A (orange signal) and two copies of CEP 9 (green signal)

Genes involved and Proteins

Gene NameCDKN2A (cyclin dependent kinase 2a / p16)
Location 9p21.3
Note CDKN2A (Cyclin Dependent Kinase Inhibitor 2A), alternative symbols included CDKN2, CDK4 inhibitor, multiple tumor suppressor 1(MTS1), TP16, p16(INK4), p16(INK4A)
Dna / Rna CDKN2A consists of three coding exons spanning over 30kb.
Protein CDKN2A gene encodes two major proteins p16(INK4) and p14(ARF) through the use of shared coding regions and alternative reading frames. Both act as tumor suppressors by regulating the cell cycle. The p16 prevents progression through the G1 cell cycle checkpoint by inhibiting cyclin-dependent kinases CDK4 and CDK6 to inactivate the retinoblastoma ( RB1) family of tumor suppressor proteins. The p14 protein acts primarily by deterring and therefore, promotes p53 protein, consequently inducing cell cycle arrest in both G1 and G2/M phases as well as initiating apoptosis.
Somatic mutations Somatic mutations of CDKN2A are common in human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after TP53. Germline mutations of CDKN2A are associated with familialmelanoma, glioblastoma and pancreatic cancer.
Gene NameCDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4))
Location 9p21.3
Note CDKN2B (Cyclin-Dependent Kinase Inhibitor 2B), alternative symbols included; Multiple Tumor Suppressor 2 (MTS2), p15(INK4B), TP15, CDKN4B inhibitor.
Protein CDKN2B encodes a cyclin-dependent kinase inhibitor "p15", which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases. The p15 protein functions as a cell growth regulator that controls cell cycle G1 progression.
Somatic mutations CDKN2B is tandemly linked to CDKN2A and frequently deleted in a significant proportion of ALL, but always in association with CDKN2A.
Gene NamePAX5 (paired box gene 5)
Location 9p13.2
Note PAX5 (Paired Box Gene 5), alternative symbols ALL3, BSAP
Protein PAX5 gene encodes a B-cell-specific activator protein (BSAP), which is a member of a class of transcription factors that contains a DNA-binding domain. It is the only member of PAX family expressed in the hematopoietic system exclusively in B-cells. Expression of PAX5 is initiated in pre-pro-B cells and maintained throughout subsequent stages of B-cell development before it is down-regulated in plasma cell. It functions both as a transcriptional activator and as a repressor on different target genes, which are involved in B-lineage development.
Germinal mutations Recently germline mutation of PAX5 gene was identified by exome sequencing in two unrelated families. The affected family members had B-cell precursor ALL and the diagnostic and relapse leukemic samples from both families demonstrated deletion of 9p through i(9)(q10) or dicentric (9q;v), both of which resulted in loss of the wild-type PAX5 allele and retention of mutated PAX5. The loss resulted in a marked reduction of normal PAX5 activity in the leukemia cells.
Somatic mutations Somatic alterations of PAX5 gene due to deletions, point mutations, or translocations occur in approximately 30% of B-ALL and in up to 50% of the high-risk BCR-ABL1 positive and Ph-like ALL subtypes. Alterations of PAX5 are not associated with an adverse outcome in children or adult B-cell ALL (Mullighan et al 2012, Shahjahani et al 2015).
Gene NameJAK2 (janus kinase 2)
Location 9p24.1
Note JAK2 (Janus kinase 2 gene), alternative symbol JTK10.
Protein JAK2 encodes a non-receptor tyrosine kinase that is involved in a specific subset of cytokine receptor signaling pathways. It has been found to be constitutively associated with the prolactin receptor ( PRLR) and is required for responses to gamma interferon ( IFNG). Upon receptor activation JAK2 phosphorylate the transcription factors "STATs" and initiate the JAK-STAT signaling pathway.
Somatic mutations Mutations of JAK1/2 have been identified in 18%-35% Down syndrome - ALL and also occur in about 10% of high-risk pediatric B- ALL patients causing a constitutive activation of the JAK-STAT pathway. The most frequent site of mutation is at R683 in the pseudokinase domain of JAK2 which is distinct from the JAK2 V617F predominant mutation seen in polycythemia vera and other myeloproliferative neoplasms (Robert et al 2012, Hunger and Mullighan 2015). The presence of JAK mutations is significantly associated with alteration of IKZF1 and rearrangement of CRLF2 signifying a high risk disease and poor outcome. ALL cases harboring CRLF2 and JAK alterations may benefit from JAK inhibitors targeted therapy.


Targeting signaling pathways in acute lymphoblastic leukemia: new insights
Harrison CJ
Hematology Am Soc Hematol Educ Program 2013;2013:118-25
PMID 24319172
Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group
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Blood 1999 Sep 1;94(5):1537-44
PMID 10477677
Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine
Hunger SP, Mullighan CG
Blood 2015 Jun 25;125(26):3977-87
PMID 25999453
Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome
Kees UR, Burton PR, Lü C, Baker DL
Blood 1997 Jun 1;89(11):4161-6
PMID 9166859
Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia
Krieger D, Moericke A, Oschlies I, Zimmermann M, Schrappe M, Reiter A, Burkhardt B
Haematologica 2010 Jan;95(1):158-62
PMID 19586936
Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial
Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE, Vora A, Mitchell CD, Harrison CJ
Lancet Oncol 2010 May;11(5):429-38
PMID 20409752
The molecular genetic makeup of acute lymphoblastic leukemia
Mullighan CG
Hematology Am Soc Hematol Educ Program 2012;2012:389-96
PMID 23233609
An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients
Nahi H, Hägglund H, Ahlgren T, Bernell P, Hardling M, Karlsson K, Lazarevic VLj, Linderholm M, Smedmyr B, Aström M, Hallbk H
Haematologica 2008 Nov;93(11):1734-8
PMID 18728022
Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia
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Cancer Cell 2012 Aug 14;22(2):153-66
PMID 22897847
The role of Pax5 in leukemia: diagnosis and prognosis significance
Shahjahani M, Norozi F, Ahmadzadeh A, Shahrabi S, Tavakoli F, Asnafi AA, Saki N
Med Oncol 2015 Jan;32(1):360
PMID 25428382
A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups
Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ
Blood 2009 Jan 1;113(1):100-7
PMID 18838613
Incidence and clinical significance of CDKN2/MTS1/P16ink4A and MTS2/P15ink4B gene deletions in childhood acute lymphoblastic leukemia
Zhou M, Gu L, Yeager AM, Findley HW
Pediatr Hematol Oncol 1997 Mar-Apr;14(2):141-50
PMID 9089742


This paper should be referenced as such :
Anwar N Mohamed
del(9p) in Acute Lymphoblastic Leukemia
Atlas Genet Cytogenet Oncol Haematol. 2017;21(7):252-255.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Translocations implicated (Data extracted from papers in the Atlas)

 del(9p) in ALL

External links

Mitelman databasedel(9p)
arrayMap (UZH-SIB Zurich)Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9837/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
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