• Sign Up

Genetics, Philadelphia Chromosome


Genetics, Philadelphia Chromosome

Article Author:
Mobeen Haider
Article Editor:
Faiz Anwer
Updated:
7/21/2020 2:05:13 PM
For CME on this topic:
Genetics, Philadelphia Chromosome CME
PubMed Link:
Genetics, Philadelphia Chromosome

Introduction

Philadelphia chromosome (Ph), named after the city where it was first described, was described for the first time by Nowell and Hungerford in 1960, in two patients who had lost the long arm of chromosome 22.[1][2][3] As the Giemsa staining improved over the decade, Rowley showed that this truncated chromosome was generated as a result of the translocation of the long arm of chromosomes 9 and 22.[2][3][4] The presence of the abnormal Ph chromosome in cells of myeloid, megakaryocytic, along with erythroid lineages pointed to the origination of the disorder in a pluripotential stem cell.[2] Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML) along with some other leukemias including acute lymphoblastic leukemia (ALL) (mostly B cell ALL, rarely T cell ALL), acute myeloid leukemia (AML), chronic neutrophilic leukemia (CNL), and mixed phenotype acute leukemia (MPAL).[4][5][6][7][8][9][10][11]

Development

The Philadelphia chromosome is generated when the proto-oncogene Abelson murine leukemia (ABL1)  gene, located on the band q34 on chromosome 9, translocates to the band q11 on chromosome 22 where the breakpoint cluster gene (BCR) is.[8][12] The translocation t(9;22)(q34;q11) results in the formation of a fusion gene called BCR-ABL1.[4]

Biochemical

The domains from BCR include:

  1. CC domain
  2. Ser/Thr kinase domain (contains a docking site Y177)
  3. Rho/GEF kinase domain

The domains from ABL1 include:

  1. SH domain (SH1/SH2)
  2. Proline-rich domain
  3. DNA & actin-binding domains

The CC domain and Y177 of BCR are essential for the activation of the ABL1 gene and have shown to be closely associated with sensitivity to tyrosine kinase inhibitor (TKI). The Rho/GEF kinase domain plays a vital role in activating differentiation in the protooncogene induced leukemogenesis.[4][13]

The SH domain of ABL1 controls the gene’s activation and deactivation, and hence this domain is an important site for pharmacologic intervention.[4]

As a result of different breakpoints in the BCR gene, that occur over quite a short DNA stretch of 5 -6 kilobases in the middle of the gene, three different BCR/ABL1 proteins are formed namely P190, P210, P230 which are usually associated with ALL, CML and CNL respectively. The numeral value represents the kDa size of the hybrid protein. There have been some reports showing correlations of P190 with CML, P210 with ALL, and P190 or P210 with AML. P230is formed by the fusion of the ABL1 gene with almost the entire BCR gene leading to the production of a 230-kDa protein.[2] It is the molecular diagnostic marker for neutrophilic-chronic myeloid leukemia (CML-N).[4][9]  

In CML, the oncoprotein P210 forms by the fusion of exon 2 (b2) or exon 3 (b3) of the BCR gene with the exon 2 (a2) of the ABL1 gene leading to the formation of either b2a2 or b3a2 11345193. Both of the transcripts produce a hybrid P210.[4] 

Function

The normal ABL Tyrosine Kinase (TK) is responsible for the activation of signal pathways that lead to increased proliferation, better viability, and changed migration as well as homing. Normally these pathways are under close regulation by different hematopoietic growth factors.[2] The ABL1 protein is a non-receptor tyrosine kinase, and it exists throughout the hematopoietic development, however myeloid maturation results in its declining levels.[4] The normal BCR gene is responsible for the oxidative burst in neutrophils.

Mechanism

The generation of BCR/ABL1 results in the constitutive activation of tyrosine kinase. It results in continued cell proliferation, inhibiting cell differentiation, and cell death. There are numerous pathways associated with the pathogenesis of BCR-ABL1 gene, including:

  • JAK2/STAT pathway: The activation of Janus Kinase (JAK) and Signal Transducers and Activation of Transcription (STAT) has been reported in P190 and P210positive leukemias. The JAK2/STAT activation in BCR/ABL1 leads to uncontrolled cell growth as well as cell survival.[14][15][16]
  • PI3K-AKT-mTOR pathway: The PI3K-AKT-mammalian target of the rapamycin (mTOR) pathway activates the c-kit positive hematopoietic stem cells; this leads to a proliferative state in CML.[17] This pathway controls cell survival, proliferation, cell cycle arrest, and has gained importance for pharmacological intervention over the past decade.[4]
  • MAPK/ERK (RAS/RAF/MEK/ERK) pathway: This pathway is involved in signal transmission from cell surface receptors to nuclear factors involved in transcription. Osteopontin (OPN), which overexpresses in BCR/ABL1, uses this pathway to maintain a leukemic microenvironment. It, in turn, promotes and maintains the proliferation and survival of leukemic cells as well as plays a role in cell differentiation and apoptosis.[4][18] 
  • TRAIL-induced apoptosis: Tumor necrosis factor (TNF)- related apoptosis-inducing ligand- TNFSF10 (TRAIL) is a death receptor ligand that normally plays a role in apoptosis. BCR/ABL1 oncogene results in the downregulation of TRAIL, hence leading to decreased apoptosis.[19][20][21][20]
  • C/EBP -mediated differentiation: CCAAT/enhancer-binding proteins (C/EBPs) are a type of transcription factors that are involved in the regulation of normal maturation of common myeloid cells to granulocyte-monocyte progenitor cells. This pathway is suppressed by the BCR/ABL1 oncogene.[4][22]

CONCURRENT GENETIC ABNORMALITIES:

In addition to the leukemogenic effect, evidence suggests that BCR/ABL1 oncogene independently leads to genomic instability.[23] A recent study has shown that several genes that predominantly play a role in the proliferation and differentiation of hematopoietic stem cells are upregulated in BCR/ABL positive CML.[24]

Common genes that are reportedly deleted in Philadelphia positive leukemias include

  • IKZF1 (7q12.2) [25]        
  • PAX5 (9p13) [26]
  • EBF1 (5q34)  [27]
  • CDKN2A/B (9p13-p23.1) [28]
  • IG (14q32.33) [28]
  • TCR (14q11.2) [28]
  • BTG1 (12q21.33) [29]

Studies have shown that primary or acquired resistance to treatment as well as relapse, can be attributed to different mutations. Rearrangements in the BCR gene can help in the prediction of response to therapy.[4]

Testing

Philadelphia chromosome is detectable with cytogenetic testing, or a reverse transcriptase PCR test can demonstrate the BCR/ABL transcripts.[2] Along with a quantitative PCR for BCR/ABL1, flow cytometry is also necessary to determine the lineage. As mentioned before, the patients usually have a concurrent genetic abnormality, so it is reasonable to get a mutational analysis done.[30][31] In addition to the above testing, liver function tests, as well as renal function tests, should be performed.[30]

Pathophysiology

This oncogene leads to constitutive activation of tyrosine kinase, which is responsible for more proliferation and better viability of the myeloid lineage cells.[4] The translocation results in decreased requirements for growth factors and provides freedom from their regulatory control.[2] This oncogene also affects cellular differentiation and apoptosis.[4]

Clinical Significance

In addition to CML, Philadelphia chromosome has shown an association with different leukemias including

  • Acute Myeloid Leukemia (AML) [4][5]
  • Acute Lymphoblastic Leukemia (ALL)  (mostly B cell ALL, rarely T cell ALL) [6][7][8]
  • Chronic Neutrophilic Leukemia (CNL) [9]
  • Mixed Phenotype Acute Leukemia (MPAL) [10]  

There have been reports of detection of the chromosomal abnormality rarely in normal healthy people.[2] Recently, a Philadelphia like ALL (Ph-like ALL) has been identified, which lacks the novel BCR-ABL1 translocation.[32]

CML: The Ph chromosome is the diagnostic feature of CML. CML has an incidence of 50 per million per year and accounts for approximately 7 to 15% of the leukemias in the adult population.[2][33] 

ALL: Philadelphia chromosome has been detected in 11 to 29 % of patients with ALL, although it is rarer with a prevalence of 1 to 3% in childhood ALL.[34][35]

AML: In patients with AML, the chromosomal abnormality has a reported incidence of less than 1.5%.[36]

MPAL: Data collected from patients diagnosed with MPAL shows that the Ph chromosome is the most frequent aberrant cytogenetic abnormality, which has led to the recognition of Ph+MPAL as a distinct disease entity with a prevalence of less than 1% of all acute leukemias.[37]

THERAPEUTIC IMPLICATIONS:

For CML, at the moment, many (five FDA approved) tyrosine kinase inhibitors, belonging to different generations, (TKI) are being used for the treatment. TKIs belonging to different generations are currently available. Frist generation TKI includes imatinib, and second-generation TKI includes bosutinib, dasatinib, and nilotinib. Third generation TKIs include ponatinib. For the chronic phase, TKI first and second-generation TKIs are included in the frontline treatments recommended.[30][38][39][40][41]

In patients diagnosed with the chronic phase of CML, risk calculations are performed before initiation of therapy. For this purpose, two different scoring systems are used.[31] One is the Sokal risk calculation, which requires the age of the patient, platelet count, the percentage of myeloblasts found in the peripheral blood and size of the spleen, whereas the Hasford risk calculation utilizes the same variables as Sokal calculator except for the percentage of myeloblasts it uses the percentage of blasts, basophils, and eosinophils.[42][43][42] For patients that have an intermediate or higher risk score, the recommendation is to consider the second-generation TKIs as the first line.[30][40][41]

For patients with treatment failure or resistance to prior lines, the third generation TKI should be used.[44] For patients with disease that is refractory to the TKI therapy, a chemotherapeutic agent omacetaxine is also a recommendation.[30][45] Studies have shown that primary or acquired resistance to treatment, as well as relapse, is attributable to different mutations. Rearrangements in the BCR gene can help in the prediction of response to therapy.

For patients with Ph+ive ALL, in addition to TKI, concurrent use of chemotherapeutic agents has shown remarkable results. For patients who are refractory to the TKI therapy and for patients with Ph+ive MPAL, a combination of alternative or advanced generation TKIs, and hematopoietic stem cell transplantation are recommendations.[4]

PROGNOSTIC SIGNIFICANCE:

The status of the Philadelphia chromosome is associated with substantially different prognoses in patients of different leukemic phenotypes. The presence of the Ph chromosome has also correlated with a higher risk of concurrent genomic abnormalities.[4]

In patients of CML, the location of the breakpoint in the BCR gene has shown an important association with prognosis. CML patients with a double Philadelphia chromosome are associated with a worse prognosis than those with a single Philadelphia chromosome.[46] The presence of concurrent genetic abnormalities is associated with a worse prognosis than in the blastic phase of CML.[2]

ALL patients, both adults, as well as children who are Ph+ive, have shown a poor prognosis in comparison to those who are Ph -ive.[8]

Patients with Ph+ive MPAL have shown a worse outcome in comparison to other leukemic phenotypes.[4]


References

[1] NOWELL PC,HUNGERFORD DA, Chromosome studies on normal and leukemic human leukocytes. Journal of the National Cancer Institute. 1960 Jul;     [PubMed PMID: 14427847]
[2] Sattler M,Griffin JD, Mechanisms of transformation by the BCR/ABL oncogene. International journal of hematology. 2001 Apr;     [PubMed PMID: 11345193]
[3] Rowley JD, Genetics. A story of swapped ends. Science (New York, N.Y.). 2013 Jun 21;     [PubMed PMID: 23788787]
[4] Kang ZJ,Liu YF,Xu LZ,Long ZJ,Huang D,Yang Y,Liu B,Feng JX,Pan YJ,Yan JS,Liu Q, The Philadelphia chromosome in leukemogenesis. Chinese journal of cancer. 2016 May 27;     [PubMed PMID: 27233483]
[5] Zhang LJ,Gan YM,Yu L, Occurrence of BCR/ABL fusion gene in a patient with acute promyelocytic leukemia. Medical oncology (Northwood, London, England). 2015 Jan;     [PubMed PMID: 25428388]
[6] Kurzrock R,Shtalrid M,Romero P,Kloetzer WS,Talpas M,Trujillo JM,Blick M,Beran M,Gutterman JU, A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia. Nature. 1987 Feb 12-18;     [PubMed PMID: 3543692]
[7] Verrma SP,Dutta TK,Vinod KV,Dubashi B,Ariga KK, Philadelphia chromosome positive pre-T cell acute lymphoblastic leukemia: a rare case report and short review. Indian journal of hematology     [PubMed PMID: 25332571]
[8] Advani AS,Pendergast AM, Bcr-Abl variants: biological and clinical aspects. Leukemia research. 2002 Aug;     [PubMed PMID: 12191565]
[9] Pane F,Frigeri F,Sindona M,Luciano L,Ferrara F,Cimino R,Meloni G,Saglio G,Salvatore F,Rotoli B, Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction) Blood. 1996 Oct 1;     [PubMed PMID: 8839830]
[10] Matutes E,Pickl WF,Van't Veer M,Morilla R,Swansbury J,Strobl H,Attarbaschi A,Hopfinger G,Ashley S,Bene MC,Porwit A,Orfao A,Lemez P,Schabath R,Ludwig WD, Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood. 2011 Mar 17;     [PubMed PMID: 21228332]
[11] Ben-Neriah Y,Daley GQ,Mes-Masson AM,Witte ON,Baltimore D, The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science (New York, N.Y.). 1986 Jul 11;     [PubMed PMID: 3460176]
[12] Koretzky GA, The legacy of the Philadelphia chromosome. The Journal of clinical investigation. 2007 Aug;     [PubMed PMID: 17671635]
[13] Chu S,Li L,Singh H,Bhatia R, BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer research. 2007 Jul 15;     [PubMed PMID: 17638918]
[14] Tao WJ,Lin H,Sun T,Samanta AK,Arlinghaus R, BCR-ABL oncogenic transformation of NIH 3T3 fibroblasts requires the IL-3 receptor. Oncogene. 2008 May 15;     [PubMed PMID: 18071309]
[15] Warsch W,Walz C,Sexl V, JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1 chronic myeloid leukemia. Blood. 2013 Sep 26;     [PubMed PMID: 23926299]
[16] Valent P, Targeting the JAK2-STAT5 pathway in CML. Blood. 2014 Aug 28;     [PubMed PMID: 25170113]
[17] Li Q,Wu Y,Fang S,Wang L,Qi H,Zhang Y,Zhang J,Li W, BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts. Cancer gene therapy. 2015 May;     [PubMed PMID: 25837664]
[18] Enciso J,Mendoza L,Pelayo R, Normal vs. Malignant hematopoiesis: the complexity of acute leukemia through systems biology. Frontiers in genetics. 2015;     [PubMed PMID: 26442108]
[19] Kuroda I,Inukai T,Zhang X,Kikuchi J,Furukawa Y,Nemoto A,Akahane K,Hirose K,Honna-Oshiro H,Goi K,Kagami K,Yagita H,Tauchi T,Maeda Y,Sugita K, BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia. Oncogene. 2013 Mar 28;     [PubMed PMID: 22665066]
[20] Zhao S,Asgary Z,Wang Y,Goodwin R,Andreeff M,Younes A, Functional expression of TRAIL by lymphoid and myeloid tumour cells. British journal of haematology. 1999 Sep;     [PubMed PMID: 10468881]
[21] Pereira WO,De Carvalho DD,Zenteno ME,Ribeiro BF,Jacysyn JF,Sardinha LR,Zanichelli MA,Hamerschlak N,Jones GE,Pagnano KB,Castro FA,Calle Y,Amarante-Mendes GP, BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy. Cell death     [PubMed PMID: 29022901]
[22] Zhang P,Iwasaki-Arai J,Iwasaki H,Fenyus ML,Dayaram T,Owens BM,Shigematsu H,Levantini E,Huettner CS,Lekstrom-Himes JA,Akashi K,Tenen DG, Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity. 2004 Dec;     [PubMed PMID: 15589173]
[23] Ilaria R Jr, Bcr/Abl, leukemogenesis, and genomic instability: a complex partnership. Leukemia research. 2002 Nov;     [PubMed PMID: 12363461]
[24] Gerber JM,Gucwa JL,Esopi D,Gurel M,Haffner MC,Vala M,Nelson WG,Jones RJ,Yegnasubramanian S, Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget. 2013 May;     [PubMed PMID: 23651669]
[25] Beer PA,Knapp DJ,Miller PH,Kannan N,Sloma I,Heel K,Babovic S,Bulaeva E,Rabu G,Terry J,Druker BJ,Loriaux MM,Loeb KR,Radich JP,Erber WN,Eaves CJ, Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression. Blood. 2015 Jan 15;     [PubMed PMID: 25370416]
[26] Nacheva EP,Brazma D,Virgili A,Howard-Reeves J,Chanalaris A,Gancheva K,Apostolova M,Valgañon M,Mazzullo H,Grace C, Deletions of immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia. BMC genomics. 2010 Jan 18;     [PubMed PMID: 20082691]
[27] Mullighan CG,Goorha S,Radtke I,Miller CB,Coustan-Smith E,Dalton JD,Girtman K,Mathew S,Ma J,Pounds SB,Su X,Pui CH,Relling MV,Evans WE,Shurtleff SA,Downing JR, Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007 Apr 12;     [PubMed PMID: 17344859]
[28] Nacheva EP,Grace CD,Brazma D,Gancheva K,Howard-Reeves J,Rai L,Gale RE,Linch DC,Hills RK,Russell N,Burnett AK,Kottaridis PD, Does BCR/ABL1 positive acute myeloid leukaemia exist? British journal of haematology. 2013 May;     [PubMed PMID: 23521501]
[29] Xie J,Wang Q,Wang Q,Yao H,Wen L,Ma L,Wu D,Chen S, High frequency of BTG1 deletions in patients with BCR-ABL1-positive acute leukemia. Cancer genetics. 2014 May;     [PubMed PMID: 24998463]
[30] Eden RE,Coviello JM, Cancer, Chronic Myelogenous Leukemia (CML, Chronic Granulocytic Leukemia) 2020 Jan;     [PubMed PMID: 30285354]
[31] Jabbour E,Kantarjian H, Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. American journal of hematology. 2018 Mar;     [PubMed PMID: 29411417]
[32] Khan M,Siddiqi R,Tran TH, Philadelphia chromosome-like acute lymphoblastic leukemia: A review of the genetic basis, clinical features, and therapeutic options. Seminars in hematology. 2018 Oct;     [PubMed PMID: 30502852]
[33] Siegel RL,Miller KD,Jemal A, Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015 Jan-Feb;     [PubMed PMID: 25559415]
[34] Schultz KR,Pullen DJ,Sather HN,Shuster JJ,Devidas M,Borowitz MJ,Carroll AJ,Heerema NA,Rubnitz JE,Loh ML,Raetz EA,Winick NJ,Hunger SP,Carroll WL,Gaynon PS,Camitta BM, Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood. 2007 Feb 1;     [PubMed PMID: 17003380]
[35] Pullarkat V,Slovak ML,Kopecky KJ,Forman SJ,Appelbaum FR, Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;     [PubMed PMID: 18156492]
[36] Soupir CP,Vergilio JA,Dal Cin P,Muzikansky A,Kantarjian H,Jones D,Hasserjian RP, Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. American journal of clinical pathology. 2007 Apr;     [PubMed PMID: 17369142]
[37] Shimizu H,Yokohama A,Hatsumi N,Takada S,Handa H,Sakura T,Nojima Y, Philadelphia chromosome-positive mixed phenotype acute leukemia in the imatinib era. European journal of haematology. 2014 Oct;     [PubMed PMID: 24750307]
[38] Hehlmann R,Lauseker M,Saußele S,Pfirrmann M,Krause S,Kolb HJ,Neubauer A,Hossfeld DK,Nerl C,Gratwohl A,Baerlocher GM,Heim D,Brümmendorf TH,Fabarius A,Haferlach C,Schlegelberger B,Müller MC,Jeromin S,Proetel U,Kohlbrenner K,Voskanyan A,Rinaldetti S,Seifarth W,Spieß B,Balleisen L,Goebeler MC,Hänel M,Ho A,Dengler J,Falge C,Kanz L,Kremers S,Burchert A,Kneba M,Stegelmann F,Köhne CA,Lindemann HW,Waller CF,Pfreundschuh M,Spiekermann K,Berdel WE,Müller L,Edinger M,Mayer J,Beelen DW,Bentz M,Link H,Hertenstein B,Fuchs R,Wernli M,Schlegel F,Schlag R,de Wit M,Trümper L,Hebart H,Hahn M,Thomalla J,Scheid C,Schafhausen P,Verbeek W,Eckart MJ,Gassmann W,Pezzutto A,Schenk M,Brossart P,Geer T,Bildat S,Schäfer E,Hochhaus A,Hasford J, Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;     [PubMed PMID: 28804124]
[39] Baccarani M,Druker BJ,Branford S,Kim DW,Pane F,Mongay L,Mone M,Ortmann CE,Kantarjian HM,Radich JP,Hughes TP,Cortes JE,Guilhot F, Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. International journal of hematology. 2014;     [PubMed PMID: 24658916]
[40] Cortes JE,Saglio G,Kantarjian HM,Baccarani M,Mayer J,Boqué C,Shah NP,Chuah C,Casanova L,Bradley-Garelik B,Manos G,Hochhaus A, Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Jul 10;     [PubMed PMID: 27217448]
[41] Nakamae H,Fukuda T,Nakaseko C,Kanda Y,Ohmine K,Ono T,Matsumura I,Matsuda A,Aoki M,Ito K,Shibayama H, Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: long-term follow-up of the Japanese subgroup of the randomized ENESTnd trial. International journal of hematology. 2018 Mar;     [PubMed PMID: 29076005]
[42] Sokal JE,Cox EB,Baccarani M,Tura S,Gomez GA,Robertson JE,Tso CY,Braun TJ,Clarkson BD,Cervantes F, Prognostic discrimination in     [PubMed PMID: 6584184]
[43] Hasford J,Pfirrmann M,Hehlmann R,Allan NC,Baccarani M,Kluin-Nelemans JC,Alimena G,Steegmann JL,Ansari H, A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. Journal of the National Cancer Institute. 1998 Jun 3;     [PubMed PMID: 9625174]
[44] Müller MC,Cervantes F,Hjorth-Hansen H,Janssen JJWM,Milojkovic D,Rea D,Rosti G, Ponatinib in chronic myeloid leukemia (CML): Consensus on patient treatment and management from a European expert panel. Critical reviews in oncology/hematology. 2017 Dec;     [PubMed PMID: 29198338]
[45] Khoury HJ,Cortes J,Baccarani M,Wetzler M,Masszi T,Digumarti R,Craig A,Benichou AC,Akard L, Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors. Leukemia     [PubMed PMID: 24650054]
[46] Kantarjian HM,Keating MJ,Talpaz M,Walters RS,Smith TL,Cork A,McCredie KB,Freireich EJ, Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. The American journal of medicine. 1987 Sep;     [PubMed PMID: 3477958]