Philadelphia chromosome-like acute lymphoblastic leukemia: A review of the genetic basis, clinical features, and therapeutic options

Khan, Maliha; Siddiqi, Rabbia; Tran, Thai Hoa

doi:10.1053/j.seminhematol.2018.05.001

Cited by 17 publications

(31 citation statements)

References 43 publications

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“…Philadelphia chromosome‐like acute lymphocytic leukemia (Ph‐L ALL) is a heterogenous subset of ALL defined within the past decade. As its name implies, this entity shares a similar gene expression profile (GEP) with Philadelphia chromosome positive ALL (Ph+ ALL), but lacks the BCR‐ABL1 fusion . This similarity in GEP is due to the presence of kinase activations, usually resulting from the presence of chromosomal micro‐deletions and insertions that result in oncogenic fusions that drive the development of both types of leukemia .…”

Section: Introductionmentioning

confidence: 99%

“…Generally speaking, Ph‐L ALL can be further divided into 3 broad groups: ABL class fusions (consisting of rearrangements in ABL1, ABL2, CSF1R, PDGFRB), JAK/STAT pathway alterations (consisting of CRLF2 ± JAK mutation, isolated JAK 1‐3 mutations, EPOR, IL2RB, TSLP ), and a miscellaneous category consisting of a multitude of less common rearrangements, including Ras pathway mutations . The frequency of these mutations varies by age group.…”

Section: Introductionmentioning

confidence: 99%

“…While always more predominant than other subtypes of Ph‐L ALL, alterations in the JAK/STAT pathway (including CRLF2 overexpression) occur more frequently with advancing age from pediatric to the young and older adult populations. The converse is true of ABL class fusions, with a decline in frequency as we progress from pediatric to adult subgroups . Averaged among all age groups, alterations in the JAK/STAT pathway are seen in >70% of Ph‐L ALL cases, with ABL class fusions occurring in roughly 10% of cases .…”

Section: Introductionmentioning

confidence: 99%

“…The converse is true of ABL class fusions, with a decline in frequency as we progress from pediatric to adult subgroups . Averaged among all age groups, alterations in the JAK/STAT pathway are seen in >70% of Ph‐L ALL cases, with ABL class fusions occurring in roughly 10% of cases . Thus, a significant majority of Ph‐L ALL could, at least in theory, be managed with JAK inhibitors (JAKi) and ABL inhibitors (ABLi).…”

Section: Introductionmentioning

confidence: 99%

“…Roberts et al found the median relapse time of Ph‐L ALL to be nearly one fifth of non‐Ph‐L ALL (122 days in Ph‐L ALL vs 555 days in non‐Ph‐L ALL) . In addition, Ph‐L ALL individuals harboring high CRLF2 expression have lower EFS and OS when compared to Ph‐L individuals lacking CRLF2 overexpression …”

Section: Introductionmentioning

confidence: 99%

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Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

Prescott

Stock

2019

Adv Cell Gene Ther

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Philadelphia chromosome-like acute lymphocytic leukemia (Ph-L ALL) is a heterogenous subset of ALL defined within the past decade. As its name implies, this entity shares a similar gene expression profile (GEP) with Philadelphia chromosome positive ALL (Ph+ ALL), but lacks the BCR-ABL1 fusion. 1-3 This similarity in GEP is due to the presence of kinase activations, usually resulting from the presence of chromosomal micro-deletions and insertions that result in oncogenic fusions that drive the development of both types of leukemia. 4-7 The vast majority of Ph-L ALL cases contain at least one activating kinase alteration and, as with Ph+ ALL, >70% of Ph-L ALL cases possess defects in the transcription factor IKZF1. 8-10 Defects in IKZF1 are associated with the development of B-cell precursor ALL (BCP-ALL) and, more specifically, high risk BCP-ALL that possess activated tyrosine kinase profiles. Interestingly, IKZF1 mutations have been described to affect downstream signaling pathways that ultimately result in treatment resistance and poor response to conventional chemotherapy. 9 It is not surprising then, that a large majority of both Ph-L and Ph+ ALL contain these mutations. Unlike Ph+ ALL, however, as mentioned above, this subset lacks the classic t[9;22].It should be noted that Ph-L ALL is an umbrella term and by no means defines a single entity. Not only is this disease subset characterized by a wide array of potentially targetable kinase and cytokine rearrangements, the definition of Ph-L ALL itself is not standardized-with the gold standard diagnosis consisting of 2 different probe sets. 1,8,11 It may be best to think of Ph-L ALL as a group of BCP-ALL that shows poor response to conventional chemotherapy with persistence of minimal residual disease and, as with Ph+ ALL, contains potentially therapeutically targetable genetic alterations. Generally speaking, Ph-L ALL can be further divided into 3 broad groups: ABL class fusions (consisting of rearrangements in ABL1, ABL2, CSF1R, PDGFRB), JAK/STAT pathway alterations (consisting of CRLF2 ± JAK mutation, isolated JAK 1-3 mutations, EPOR, IL2RB, TSLP), and a miscellaneous category consisting of a multitude of less common rearrangements, including Ras pathway mutations. 3,4,8 The frequency of these mutations varies by age group. While always more predominant than other subtypes of Ph-L ALL, alterations in the JAK/STAT pathway (including CRLF2 overexpression) occur more frequently with advancing age from pediatric to the young and older adult populations. The converse is true of ABL class fusions, with a decline in frequency as we progress from pediatric to adult subgroups. 3,10 Averaged among all age groups, alterations in the JAK/ STAT pathway are seen in >70% of Ph-L ALL cases, with ABL class fusions occurring in roughly 10% of cases. 3,12 Thus, a significant majority of Ph-L ALL could, at least in theory, be managed with JAK inhibitors (JAKi) and ABL inhibitors (ABLi). Individuals with Ph-L ALL tend to have higher WBC counts at diagnosis, higher rates of induct...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

Prescott

Stock

2019

Adv Cell Gene Ther

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Philadelphia‐like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia

Ballesteros

Yunis

García³

et al. 2021

Cancer Reports

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Background: Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America.Aim: This study evaluated the frequency and clinical and biological characteristics of Ph-like ALL in a pediatric cancer center in Colombia. Methods:The Ph-like genetic profile was analyzed by a low-density array (LDA).Samples from patients with Ph-like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto-oncogene 1, nonreceptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification.Results: Data from 121 patients were analyzed. Fifteen patients (12.4%) had Ph-like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph-like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%).Conclusions: Ph-like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.Adriana Linares and Luz Karime Yunis contributed equally as first authors.

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Treatment of Ph-Like Acute Lymphoblastic Leukemia

Tran

Tasian

2022

Clinical Management of Acute Lymphoblastic Leukemia

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Philadelphia chromosome-like acute lymphoblastic leukemia: A review of the genetic basis, clinical features, and therapeutic options

Cited by 17 publications

References 43 publications

Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

Philadelphia‐like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia

Treatment of Ph-Like Acute Lymphoblastic Leukemia

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